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9. Persistence of Anti-SARS-CoV-2 Antibodies in Non-Hospitalized COVID-19 Convalescent Health Care Workers

Author

Bruni, M, Cecatiello, V, Diaz-Basabe, A, Lattanzi, G, Mileti, E, Monzani, S, Pirovano, L, Rizzelli, F, Visintin, C, Bonizzi, G, Giani, M, Lavitrano, M, Faravelli, S, Forneris, F, Caprioli, F, Pelicci, P, Natoli, G, Pasqualato, S, Mapelli, M, Facciotti, F, Bruni M, Cecatiello V, Diaz-Basabe A, Lattanzi G, Mileti E, Monzani S, Pirovano L, Rizzelli F, Visintin C, Bonizzi G, Giani M, Lavitrano M, Faravelli S, Forneris F, Caprioli F, Pelicci PG, Natoli G, Pasqualato S, Mapelli M, Facciotti F, Bruni, M, Cecatiello, V, Diaz-Basabe, A, Lattanzi, G, Mileti, E, Monzani, S, Pirovano, L, Rizzelli, F, Visintin, C, Bonizzi, G, Giani, M, Lavitrano, M, Faravelli, S, Forneris, F, Caprioli, F, Pelicci, P, Natoli, G, Pasqualato, S, Mapelli, M, Facciotti, F, Bruni M, Cecatiello V, Diaz-Basabe A, Lattanzi G, Mileti E, Monzani S, Pirovano L, Rizzelli F, Visintin C, Bonizzi G, Giani M, Lavitrano M, Faravelli S, Forneris F, Caprioli F, Pelicci PG, Natoli G, Pasqualato S, Mapelli M, and Facciotti F

Abstract

Although antibody response to SARS-CoV-2 can be detected early during the infection, several outstanding questions remain to be addressed regarding the magnitude and persistence of antibody titer against different viral proteins and their correlation with the strength of the immune response. An ELISA assay has been developed by expressing and purifying the recombinant SARS-CoV-2 Spike Receptor Binding Domain (RBD), Soluble Ectodomain (Spike), and full length Nucleocapsid protein (N). Sera from healthcare workers affected by non-severe COVID-19 were longitudinally collected over four weeks, and compared to sera from patients hospitalized in Intensive Care Units (ICU) and SARS-CoV-2-negative subjects for the presence of IgM, IgG and IgA antibodies as well as soluble pro-inflammatory mediators in the sera. Non-hospitalized subjects showed lower antibody titers and blood pro-inflammatory cytokine profiles as compared to patients in Intensive Care Units (ICU), irrespective of the antibodies tested. Noteworthy, in non-severe COVID-19 infections, antibody titers against RBD and Spike, but not against the N protein, as well as pro-inflammatory cytokines decreased within a month after viral clearance. Thus, rapid decline in antibody titers and in pro-inflammatory cytokines may be a common feature of non-severe SARS-CoV-2 infection, suggesting that antibody-mediated protection against re-infection with SARS-CoV-2 is of short duration. These results suggest caution in using serological testing to estimate the prevalence of SARS-CoV-2 infection in the general population.

Published
2020

15. CDH1 mutation distribution and type suggests genetic differences between the etiology of orofacial clefting and gastric cancer

Author

Selvanathan, A, Nixon, CY, Zhu, Y, Scietti, L, Forneris, F, Moreno Uribe, LM, Lidral, AC, Jezewski, PA, Mulliken, JB, Murray, JC, Buckley, MF, Cox, TC, Roscioli, T, Selvanathan, A, Nixon, CY, Zhu, Y, Scietti, L, Forneris, F, Moreno Uribe, LM, Lidral, AC, Jezewski, PA, Mulliken, JB, Murray, JC, Buckley, MF, Cox, TC, and Roscioli, T

Abstract

Pathogenic variants in CDH1, encoding epithelial cadherin (E-cadherin), have been implicated in hereditary diffuse gastric cancer (HDGC), lobular breast cancer, and both syndromic and non-syndromic cleft lip/palate (CL/P). Despite the large number of CDH1 mutations described, the nature of the phenotypic consequence of such mutations is currently not able to be predicted, creating significant challenges for genetic counselling. This study collates the phenotype and molecular data for available CDH1 variants that have been classified, using the American College of Medical Genetics and Genomics criteria, as at least ‘likely pathogenic’, and correlates their molecular and structural characteristics to phenotype. We demonstrate that CDH1 variant type and location differ between HDGC and CL/P, and that there is clustering of CL/P variants within linker regions between the extracellular domains of the cadherin protein. While these differences do not provide for exact prediction of the phenotype for a given mutation, they may contribute to more accurate assessments of risk for HDGC or CL/P for individuals with specific CDH1 variants.

Published
2020

17. Contributors

Author

Abbott, Catherine Anne, primary, Abraham, Carmela R., additional, Adachi, Hideki, additional, Adachi, Osao, additional, Adam, Zach, additional, Adams, Michael W.W., additional, Adang, Michael J., additional, Adham, Ibrahim M., additional, Aducci, Patrizia, additional, Agard, David A., additional, Agranovsky, Alexey A., additional, Akamatsu, Tetsuya, additional, Akiyama, Yoshinori, additional, Albrechtsen, Reidar, additional, Alejo, Alí, additional, Amberg, Sean M., additional, Amerik, Alexander Y., additional, Amparyup, Piti, additional, Andrade, Felipe, additional, Andrés, Germán, additional, Andrews, Daniel M., additional, Andrews, Robert K., additional, Antalis, Toni M., additional, Anthony, Colin S., additional, Aoki, Naoya, additional, Apte, Suneel S., additional, Arima, Kazunari, additional, Arlaud, Gérard, additional, Arni, Raghuvir Krishnaswamy, additional, Arnoux, Pascal, additional, Aronson, Nathan N., additional, Arthur, Michel, additional, Asano, Yasuhisa, additional, Ascenzi, Paolo, additional, Assakura, Marina T., additional, Auld, David S., additional, Ávila, Veridiana de Melo Rodrigues, additional, Avilés, Francesc X., additional, Awad, William M., additional, Bachhawat, Anand K., additional, Bai, Shan, additional, Baird, Teaster T., additional, Bajaj, S. Paul, additional, Baker, Susan C., additional, Banbula, Agnieszka, additional, Barrett, Alan J., additional, Barrowman, Jemima, additional, Bartlett, John D., additional, Bartsch, Jörg W., additional, Baschuk, Nikola, additional, Baskova, Isolda P., additional, Batra, Jyotsna, additional, Bauer, Karl, additional, Baumann, Ulrich, additional, Baumeister, Wolfgang, additional, Bauvois, Cédric, additional, Bayés, Alex, additional, Beauvais, Anne, additional, Becker-Pauly, Christoph, additional, Begley, Tadhg P., additional, Békés, Miklós, additional, Belas, Robert, additional, Beleford, Daniah, additional, Beppu, Teruhiko, additional, Bergmann, Ernst M., additional, Bernard, Bruno A., additional, Bernard, Dominique, additional, Berndt, Michael C., additional, Berruti, Giovanna, additional, Berry, Colin, additional, Bertenshaw, Greg P., additional, Betzel, Christian, additional, Bhaskarla, Chetana, additional, Bhosale, Manoj, additional, Bierbaum, Gabriele, additional, Bjarnason Jón, B., additional, Blaber, Michael, additional, Blackman, Michael J., additional, Blinkovsky, Alexander, additional, Boeke, Jef D., additional, Bogyo, Matthew, additional, Bohn, Stefan, additional, Boileau, Guy, additional, Boland, Mike, additional, Bolken, Tové C., additional, Bond, Judith S., additional, Bondeson, Jan, additional, Bordallo, Javier, additional, Borelli, Claudia, additional, Botelho, Tiago O., additional, Bott, Richard R., additional, Bourne, David G., additional, Bovenschen, Niels, additional, Bradshaw, Ralph A., additional, Breddam, Klaus, additional, Brew, Keith, additional, Brindley, Paul J., additional, Brinkman, Diane L., additional, Britton, Collette, additional, Broadbent, Jeff R., additional, Broadhurst, Anne, additional, Brómme, Dieter, additional, Broom, Murray, additional, Brown, Jeremy S., additional, Brown, Mark A., additional, Bruchhaus, Iris, additional, Burleigh, Barbara A., additional, Burns, Kristin E., additional, Burrows, James F., additional, Butler, Michael J., additional, Buttle, David J., additional, Byrd, Chelsea M., additional, Byun, Tony, additional, Cadel, Sandrine, additional, Caffrey, Conor R., additional, Cal, Santiago, additional, Caldentey, Javier, additional, Candela, Thomas, additional, Capasso, Clemente, additional, Capriogilio, Daniel R., additional, Carginale, Vincenzo, additional, Carmona, Adriana Karaoglanovic, additional, Carruthers, Vern B., additional, Castellino, Francis J., additional, Catanese, Joseph J., additional, Caterson, Bruce, additional, Caughey, George H., additional, Cawley, Naimh X., additional, Cawston, Tim E., additional, Cazzulo, Juan José, additional, Chai, Jijie, additional, Chai, Karl X., additional, Chaim, Olga Meiri, additional, Chang, L.S., additional, Chao, Julie, additional, Chapot-Chartier, Marie-Pierre, additional, Charli, Jean-Louis, additional, Charlier, Paulette, additional, Chave, Karen J., additional, Chen, Jian-Min, additional, Chen, Jinq-May, additional, Chen, Li-Mei, additional, Chen, Ya-Wen, additional, Chen, Yu-Yen, additional, Chevrier, Bernard, additional, Chich, Jean-François, additional, Chien, Jeremy, additional, Chimalapati, Suneeta, additional, Cho, Ki Joon, additional, Choi, Kwan Yong, additional, Chuang, Woei-Jer, additional, Chung, Chin Ha, additional, Chung, Ivy Yeuk Wah, additional, Clamagirand, Christine, additional, Clark, Ian M., additional, Clarke, Adrian K., additional, Clarke, Nicola E., additional, Clarke, Steven Gerard, additional, Clauziat, Philippe, additional, Clements, Judith A., additional, Coffinier, Catherine, additional, Cohen, Paul, additional, Colige, Alain, additional, Collignon, Anne, additional, Colloms, Sean D., additional, Conzelmann, Andreas, additional, Coombs, Graham H., additional, Cooney, Jakki C., additional, Cooper, Jonathan B., additional, Cooper, Max D., additional, Copeland, Nikki A., additional, Cottrell, Graeme S., additional, Coyle, Joseph T., additional, Craik, Charles S., additional, Creemers, John W.M., additional, Cretu, Daniela, additional, Croce, Jenifer, additional, Cross, Keith J., additional, Cueva, Rosario, additional, Cui, Sheng, additional, Cunha, Luis, additional, Cutting, Simon, additional, d’Enfert, Christophe, additional, D’Orchymont, Hugues, additional, Dahlbäck, Björn, additional, Dai, Shujia, additional, Dalbey, Ross E., additional, Dalton, John P., additional, Dando, Pam M., additional, Daniel, R.M., additional, Danilov, Sergei M., additional, Davies, Donna E., additional, De Araujo, Heloisa S., additional, De los Santos, Teresa, additional, de Luca, Viviana, additional, De Meester, Ingrid, additional, de Oliveira, Ana Karina, additional, de Oliveira, Eduardo Brandt, additional, De Oliveira, Pedro Lagerblad, additional, de Vos, Sarah, additional, Declercq, Jeroen, additional, Declercq, Wim, additional, Deghmane, Ala-Eddine, additional, Dekker, Niek, additional, Del Prete, Sonia, additional, Del Rosal, Marina, additional, Delmas, Bernard, additional, DeLotto, Robert, additional, Demidyuk, Ilya V., additional, Denison, Mark R., additional, Deussing, Jan M., additional, Devi, Lakshmi A., additional, Diamandis, Eleftherios P., additional, Diaz, Isabel, additional, Díaz-Perales, Araceli, additional, Dijkstra, Bauke W., additional, Ding, Yan, additional, Dixon, Jack E., additional, Dodt, Johannes, additional, Dokland, Terje, additional, Dolenc, Iztok, additional, Dong, Ningzheng, additional, Dong, Tran Cat, additional, Dong, Ying, additional, Dongre, Mitesh, additional, Donovan, Mark, additional, Dore, Timothy M., additional, Dorstyn, Loretta, additional, Dou, Hong, additional, Dou, Zhicheng, additional, Dougall, Annette M., additional, Drag, Marcin, additional, Dudley, Edward G., additional, Dunn, Ben M., additional, Dupuy, Bruno, additional, Duque-Magalhāes, Maria Conceicāo, additional, Durá, M. Asunción, additional, Eeckhout, Yves, additional, Eijsink, Vincent, additional, Eisen, Arthur Z., additional, Eissa, Azza, additional, Eklund, Sandra, additional, Eletr, Ziad M., additional, Ellis, Vincent, additional, Engel, Wolfgang, additional, Erdös, Ervin G., additional, Escalante, Teresa, additional, Estell, David A., additional, Etscheid, Michael, additional, Evans, Herbert J., additional, Everett, Roger D., additional, Faesen, Alex C., additional, Fahrenholz, Falk, additional, Fanjul-Fernández, Miriam, additional, Farady, Christopher J., additional, Feller, Georges, additional, Feng, Hong, additional, Fenster, Kurt M., additional, Férec, Claude, additional, Ferrari, Silvia, additional, Fingleton, Barbara, additional, Fisher, Jed F., additional, Fives-Taylor, Paula M., additional, Fong, Loren G., additional, Forneris, F., additional, Forster, Brian M., additional, Forster, Friedrich, additional, Foster, Simon J., additional, Foulon, Thierry, additional, Foundling, Stephen I., additional, Fox, Jay William, additional, Franzetti, Bruno, additional, Frasch, Alejandra P., additional, Freeze, Hudson H., additional, Frère, Jean-Marie, additional, Frey, Teryl K., additional, Fricke, Beate, additional, Fricker, Lloyd D., additional, Fridman, Rafael, additional, Froelich, Christopher J., additional, Fröhlich, Camilla, additional, Fu, Hsueh-Liang, additional, Fuhrmann, Cynthia N., additional, Fujimura, Satoshi, additional, Fujiwara, Hiroshi, additional, Fukushima, Jun, additional, Fukuyama, Keiichi, additional, Fuller, Robert S., additional, Fusek, Martin, additional, Gaboriaud, Christine, additional, Gache, Christian, additional, Gakh, Oleksandr, additional, Gal, Peter, additional, Gao, Junjun, additional, García-Sastre, Adolfo, additional, Gardiner, Donald L., additional, Gatehouse, John A., additional, Gaucher, G.M., additional, Gauthier, Francis, additional, Ghuysen, Jean-Marie, additional, Gibson, Wade, additional, Gillies, Jennifer, additional, Glaser, Elzbieta, additional, Glaser, Fabian, additional, Glickman, Michael H., additional, Goettig, Peter, additional, Goffin, Colette, additional, Gohda, Eiichi, additional, Goldberg, Alfred L., additional, Goldberg, Daniel E., additional, Goldberg, Gregory I., additional, Goldfarb, Nathan E., additional, Gomis-Rüth, F. Xavier, additional, Gopal, B., additional, Gorbalenya, Alexander E., additional, Gordon, Stuart G., additional, Gorrell, Mark D., additional, Götz, Friedrich, additional, Goulas, Theodoros, additional, Gouzy-Darmon, Cécile, additional, Govind, K., additional, Gráf, Lászlo, additional, Granados, Robert R., additional, Gräwert, Melissa Ann, additional, Gray, Douglas A., additional, Graycar, Thomas P., additional, Green, Jonathan A., additional, Gremski, Luiza Helena, additional, Groll, Michael, additional, Gromova, Tania Yu, additional, Gros, P., additional, Grubman, Marvin J., additional, Grunden, Amy M., additional, Gudmundsdóttir, Ágústa, additional, Guinand, Micheline, additional, Gully, Djamel, additional, Gustchina, Alla, additional, Gutiérrez, José María, additional, Ha, Byung Hak, additional, Haeggström, Jesper Z., additional, Hageman, James H., additional, Haiko, Johanna, additional, Hailfinger, Stephan, additional, Haitchi, Hans Michael, additional, Han, Ji Seon, additional, Hanquez, Chantal, additional, Harada, Minoru, additional, Hara-Nishimura, Ikuko, additional, Harboe, Marianne, additional, Härd, Torleif, additional, Harris, David A., additional, Hassiepen, Ulrich, additional, Hata, Shoji, additional, Hattori, Akira, additional, He, Rong-Qiao, additional, Heck, Albert J.R., additional, Hendricks, Dirk F., additional, Henrich, Bernhard, additional, Henriet, Patrick, additional, Hernández-Arana, Andrés, additional, Herrera-Camacho, Irma, additional, Heussipp, Gerhard, additional, Hibino, Toshihiko, additional, Hicks, P.M., additional, Hillman, Bradley I., additional, Hiraoka, B. Yukihiro, additional, Hiratake, Jun, additional, Hizukuri, Yohei, additional, Ho, Heng-Chien, additional, Hoa, Ngo Thi, additional, Hochstrasser, Mark, additional, Hodge, Kathryn M., additional, Hofmann, Theo, additional, Hohn, Thomas, additional, Hoidal, John R., additional, Höltje, Joachim-Volker, additional, Homma, Koichi J., additional, Honek, John F., additional, Hook, Vivian Y.H., additional, Hooper, John D., additional, Hooper, Nigel M., additional, Hosoi, Kazuo, additional, Howe, Christopher J., additional, Hruby, Dennis E., additional, Hseih, James J.-D., additional, Hsu, Chun-Chieh, additional, Huang, Tony T., additional, Huang, Tur-Fu, additional, Huet, Yoann, additional, Hughes, Clare, additional, Hugonnet, Jean-Emmanuel, additional, Huston, Adrienne L., additional, Ibrahim-Granet, Oumaïma, additional, Ichishima, Eiji, additional, Ikehara, Yukio, additional, Inagami, Tadashi, additional, Ingram, Jessica, additional, Isaac, R.E., additional, Isaya, Grazia, additional, Isaza, Clara E., additional, Ishii, Shin-ichi, additional, Isnard, Amandine, additional, Ito, Kiyoshi, additional, Ito, Koreaki, additional, Itoh, Yoshifumi, additional, Iturrioz, Xavier, additional, Iwanaga, Sadaaki, additional, Jack, Ralph W., additional, Jackson, Mel C., additional, James, Michael N.G., additional, Janata, Jiří, additional, Janoir, Claire, additional, Janska, Hanna, additional, Jarrell, Ken F., additional, Jaskolski, Mariusz, additional, Jaswal, Sheila S., additional, Jean, Ying Y., additional, Jenne, Dieter E., additional, Jeon, Young Joo, additional, Jiang, Ping, additional, Johnson, John E., additional, Johnson, Michael D., additional, Johnston, James A., additional, Jones, Amanda, additional, Jones, Elizabeth W., additional, Joudiou, Carine, additional, Juliano, Luiz, additional, Jung, Hea-Jin, additional, Jupp, Ray, additional, Kagawa, Todd F., additional, Kalbacher, Hubert, additional, Kamata, Yayoi, additional, Kaminogawa, Shuichi, additional, Kamio, Yoshiyuki, additional, Kaneda, Makoto, additional, Kang, Sung Gyun, additional, Kang, Sung Hwan, additional, Kania, Mary, additional, Kantyka, Tomasz, additional, Kanzawa, Nobuyuki, additional, Karim, Abdulkarim Y., additional, Kasumi, Takafumi, additional, Kataoka, Hiroaki, additional, Kaur, Hardeep, additional, Kawabata, Shun-Ichiro, additional, Kawaguchi, Mari, additional, Kay, John, additional, Kaynar, Murat, additional, Keiler, Kenneth C., additional, Kelly, R.M., additional, Kenton, Nathaniel T., additional, Kerr, Michael A., additional, Kersse, Kristof, additional, Kervinen, Jukka, additional, Kessler, Benedikt M., additional, Kessler, Efrat, additional, Khoronen, Timo K., additional, Kidd, Simon, additional, Kikkert, Marjolein, additional, Kilian, Mogens, additional, Kim, Do-Hyung, additional, Kim, Doyoun, additional, Kim, Eunice EunKyeong, additional, Kim, In Seop, additional, Kim, Jung-Gun, additional, Kim, Kyeong Kyu, additional, Kim, Kyung Hyun, additional, Kimber, Matthew S., additional, Kimura, Yukio, additional, Kirschke, Heidrun, additional, Kiso, Yoshiaki, additional, Kleanthous, Colin, additional, Klein, Jürgen R., additional, Klemba, Michael, additional, Kmiec, Beata, additional, Kobayashi, Hideyuki, additional, Kodama, Hiroyuki, additional, Koelsch, Gerald, additional, Kok, Jan, additional, Kolattukody, P.E., additional, Kolb, Fabrice A., additional, Kolmar, Harald, additional, Komori, Yumiko, additional, Konvalinka, Jan, additional, Korkmaz, Brice, additional, Kostrov, Sergey V., additional, Kräusslich, Hans-Georg, additional, Krczal, Gabi, additional, Kress, Lawrence F., additional, Kristjánsson, Magnüs Már, additional, Kučera, Tomáš, additional, Kukday, Sayali S., additional, Kumagai, Hidehiko, additional, Kumar, Sharad, additional, Kumarasiri, Malika, additional, Kumazaki, Takashi, additional, Kümmerer, Beate M., additional, Kuno, Kouji, additional, Kurkinen, Markku, additional, Kutejová, Eva, additional, Kveiborg, Marie, additional, Kwarciak, Agnieszka, additional, Laakkonen, Liisa, additional, Labrou, Nikolaos E., additional, Laing, Gavin D., additional, Lamppa, Gayle, additional, Langer, Thomas, additional, Laursen, Richard A., additional, Lawrenson, Richard A., additional, Layne, Matthew D., additional, Le Bonniec, Bernard F., additional, Leal, María C., additional, Lechan, Ronald M., additional, Lee, David H., additional, Lee, Irene, additional, Lee, Jae, additional, Lee, Kye Joon, additional, Lee, Soohee, additional, Lei, Xiaobo, additional, Leis, Jonathan, additional, LeMosy, Ellen K., additional, Lepage, Thierry, additional, Leppla, Stephen H., additional, Lesner, Adam, additional, Lessard, Ivan A.D., additional, Lhomond, Guy, additional, Li, Huilin, additional, Li, Shu-Ming, additional, Li, Weiguo, additional, Liao, Ta-Hsiu, additional, Liddington, Robert C., additional, Lieber, Toby, additional, Lijnen, H.R., additional, Lima, Christopher D., additional, Lin, Chen-Yong, additional, Lin, Gang, additional, Lin, Ming T., additional, Lin, Xinli, additional, Lin, Yee-Shin, additional, Lindsay, L.L., additional, Lipscomb, William N., additional, Little, John W., additional, Liu, Ching-Chuan, additional, Liu, Chuan-ju, additional, Lively, Mark O., additional, Livnat-Levanon, Nurit, additional, Ljungdahl, Per O., additional, Llorens-Cortes, Catherine, additional, Lobel, Peter, additional, Loh, Y. Peng, additional, Lohi, Jouko, additional, Lomonossoff, G.P., additional, Looze, Yvan, additional, López-Otin, Carlos, additional, Lopez-Quezada, Landys, additional, Loukas, Alex, additional, Lu, Long-Sheng, additional, Lundwall, Áke, additional, Luo, Liu-Ying, additional, Lupas, Andrei, additional, Luthe, Dawn S., additional, Lynch, Nicholas J., additional, Lyons, Peter J., additional, MacKay, Vivian L., additional, Macleod, Jesica M. Levingston, additional, Magdolen, Viktor, additional, Mainardi, Jean-Luc, additional, Mäkinen, Kauko K., additional, Mallari, Jeremy P., additional, Manandhar, Surya P., additional, Mandelbaum, Fajga R., additional, Manicone, Anne M., additional, Mansfeld, Johanna, additional, Marcotrigiano, Joseph, additional, Mares, Michael, additional, Marfany, Gemma, additional, Markland, Francis S., additional, Marokházi, Judith, additional, Marquis, Hélène, additional, Marr, Robert A., additional, Martegani, Enzo, additional, Martin, Erik W., additional, Martinez, Manuel, additional, Martins, L. Miguel, additional, Maruyama, Masato, additional, Maruyama, Masugi, additional, Maruyama, Sususmu, additional, Masaki, Takeharu, additional, Massoumi, Ramin, additional, Mathew, Rency T., additional, Matrisian, Lynn M., additional, Matsuda, Yoshihiro, additional, Matsushita, Osamu, additional, Matuschek, Marco, additional, Matušková, Anna, additional, Matúz, Krisztina, additional, Mauch, Cornelia, additional, Maurizi, Michael R., additional, Mayr, Lorenz M., additional, McCafferty, Dewey G., additional, McDonald, J. Ken, additional, McKerrow, James H., additional, McMillan, David, additional, Mecham, Robert P., additional, Mehta, Darshini P., additional, Meisinger, Chris, additional, Mellors, Alan, additional, Melton, Roger G., additional, Melvin, Jeffrey A., additional, Ménard, Robert, additional, Menéndez-Arias, Luis, additional, Menezes, Milene C., additional, Mesecar, Andrew, additional, Mesnage, Stéphane, additional, Meyer, Diane H., additional, Meyers, Gregor, additional, Michaelis, Susan, additional, Michalska, Karolina, additional, Mielicki, Wojciech P., additional, Mierau, Igor, additional, Mikoulinskaia, Galina V., additional, Miller, Charles G., additional, Miller, Lydia K., additional, Mills, John, additional, Mills, Kenneth V., additional, Min, Jinrong, additional, Mistou, Michel-Yves, additional, Misumi, Yoshio, additional, Miyoshi, Shin-ichi, additional, Mizutani, Shigehiko, additional, Mobashery, Shahriar, additional, Mochizuki, Satsuki, additional, Mock, William L., additional, Möhrlen, Frank, additional, Moiré, Nathalie, additional, Monahan, Paul E., additional, Moncada-Pazos, Angela, additional, Monnet, Véronique, additional, Monod, Michel, additional, Montecucco, Cesare, additional, Morelli, Laura, additional, Mori, Sumiko, additional, Morita, Takashi, additional, Morrissey, James H., additional, Morse, Richard J., additional, Mort, John S., additional, Mortensen, Uffe H., additional, Morty, Rory E., additional, Moss, Joel, additional, Motoshima, Hidemasa, additional, Mottram, Jeremy C., additional, Moura-da-Silva, Ana M., additional, Mudgett, Mary Beth, additional, Mundt, Egbert, additional, Murakami, Kazuo, additional, Murakami, Mario Tyago, additional, MurakamiMurofoshi, Kimiko, additional, Murao, Sawao, additional, Murphy, Gillian, additional, Murthy, M.R.N., additional, Muta, Tatsushi, additional, Myburgh, Elmarie, additional, Mzhavia, Nino, additional, Nabi, A.H.M. Nurun, additional, Nagase, Hideaki, additional, Nagle, Michael W., additional, Nägler, Dorit K., additional, Naik, Rajesh R., additional, Nair, Divya B., additional, Nakai, Toshiki, additional, Nakajima, Yoshitaka, additional, Nakamura, Yukio, additional, Nakatogawa, Hitoshi, additional, Nakayama, Toru, additional, Nalivaeva, Natalia N., additional, Nandi, Dipankar, additional, Nascimento-Silva, Maria Clara Leal, additional, Nasmyth, Kim, additional, Nathan, Carl F., additional, Navarro-García, Fernando, additional, Naves, Dayane Lorena, additional, Nedialkova, Danny D., additional, Neuman, Keir C., additional, Nguyen, Jeffrey-Tri, additional, Nguyen, Ky-Anh, additional, Niemirowicz, Gabriela T., additional, Nikai, Toshiaki, additional, Nishi, Eiichiro, additional, Nishii, Wataru, additional, Nishiyama, Makoto, additional, Nishiyama, Yasuhiro, additional, Noda, Masatoshi, additional, Nomura, Seiji, additional, Norioka, Shigemi, additional, Nsangou, Desire M.M., additional, O’Brien, Amornrat, additional, O’Connor, Michael B., additional, Oda, Kohei, additional, Odinokova, Irina V., additional, Oetjen, Joyce, additional, Ogura, Teru, additional, Ohman, Dennis E, additional, Ohsumi, Yoshinori, additional, Ojha, Mukti, additional, Okabe, Akinobu, additional, Okada, Yasunori, additional, Okamoto, Keinosuke, additional, Okuda, Kenji, additional, Okumura, Nobuaki, additional, Okuno, Takashi, additional, Oleson, Kjeld, additional, Oliveira de Giuseppe, Priscila, additional, Olivier, Martin, additional, Ono, Yasuko, additional, Oroszlan, Stephen, additional, Ota, Nobuyuki, additional, Ovadia, Michael, additional, O-Wang, Jiyang, additional, Oxvig, Claus, additional, Packer, Jeremy C.L., additional, Padilla-López, Sergio, additional, Paetzel, Mark, additional, Page, Michael J., additional, Page-McCaw, Andrea, additional, Paine, Mark J.I., additional, Park, Byoung Chul, additional, Park, Eunyong, additional, Park, John E., additional, Park, Pyong Woo, additional, Park, Sung Goo, additional, Parkin, Kirk L., additional, Parks, William C, additional, Paschoalin, Thaysa, additional, Pastore, Annalisa, additional, Patananan, Alexander Nikolich, additional, Paul, Sudhir, additional, Paulson, Henry L., additional, Pawel-Rammingen, Ulrich von, additional, Pearce, David A., additional, Pearson, Mark S., additional, Pei, Duanqing, additional, Pejler, Gunnar, additional, Pemberton, Alan D., additional, Peng, Jianhao, additional, Pernier, Julien, additional, Peters, Jan-Michael, additional, Pfirrmann, Thorsten, additional, Pham, Viet-Laï, additional, Pichová, Iva, additional, Pickering, Darren, additional, Piesse, Christophe, additional, Pignol, David, additional, Pike, Robert N., additional, Pinck, Lothaire, additional, Pirkle, Hubert, additional, Pitot, Henry C., additional, Plaut, Andrew G., additional, Ploegh, Hidde, additional, Polgár, László, additional, Porter, Corrine, additional, Postina, Rolf, additional, Potempa, Jan, additional, Poulsen, Knud, additional, Power, Scott D., additional, Pratt, Rex. F., additional, Prehna, Gerd, additional, Prévost, Gilles, additional, Pshezhetsky, Alexey V., additional, Qasim, Mohammad A., additional, Qian, Feng, additional, Qiu, Jiazhou, additional, Quesada, Víctor, additional, Radisky, Evette S., additional, Rader, Stephen D., additional, Raman, Kavita, additional, Ramsay, Andrew J., additional, Rancourt, Derrick E., additional, Ranjit, Najju, additional, Rao, Narayanam V., additional, Ratia, Kiira, additional, Rawlings, Neil D., additional, Rawson, Robert B., additional, Reddy, Vijay, additional, Redman, Colvin M., additional, Regonesi, Maria Elena, additional, Reichert, Andreas S., additional, Reichl, Antonia P., additional, Remaut, Han, additional, Remington, S. James, additional, Renatus, Martin, additional, Reverter, David, additional, Reynolds, Eric C., additional, Rholam, Mohamed, additional, Rice, Charles M., additional, Ridky, Todd W., additional, Riezman, Howard, additional, Rijken, D.C., additional, Rio, Marie-Christine, additional, Ritchie, Alison, additional, Robert-Baudouy, Janine, additional, Robinson, Mark W., additional, Robinson, Michael, additional, Rodriguez-Romero, Adela, additional, Rodriques, Renata Santos, additional, Rogers, John C., additional, Rojas, Camilo, additional, Romesberg, Floyd E., additional, Roper, David J., additional, Rosas-Murrieta, Nora, additional, Rose, A.M., additional, Rosenthal, Philip J., additional, Rosing, J., additional, Rossetto, Ornella, additional, Rossi, Véronique, additional, Roth, Richard A., additional, Rottensteiner, Hanspeter, additional, Rowan, Andrew D., additional, Rozanov, Mikhail, additional, Rucavado, Alexandra, additional, Ruecker, Andrea, additional, Rul, Françoise, additional, Rümenapf, Till, additional, Russo, Ilaria, additional, Ryan, Martin D., additional, Sacco, Elena, additional, Sadler, J. Evan, additional, Saenger, W., additional, Sahl, Hans-Georg, additional, Sajid, Mohammed, additional, Sakaguchi, Masayoshi, additional, Sakiyama, Fumio, additional, Salas, Maria L., additional, Salgado, Maria Cristina O., additional, Salvesen, Guy S., additional, Sánchez, Edith, additional, Sanchez, Eladio F., additional, Sang, Qing-Xiang Amy, additional, Sankaran, Krishnan, additional, Sarkar, Susanta K., additional, Sarras, Michael P., additional, Sasagawa, Yoshikiyo, additional, Satohiko, Araki, additional, Sauvage, Eric, additional, Saveanu, Loredana, additional, Savithri, H.S., additional, Sawada, Hitoshi, additional, Sawers, R. Gary, additional, Scarisbrick, Isobel A., additional, Schaller, Andreas, additional, Scheer, Justin M., additional, Scheiflinger, Friedrich, additional, Schiene-Fischer, Cordelia, additional, Schlomann, Uwe, additional, Schlösser, Manfred, additional, Schmaier, Alvin H., additional, Schmidt, Walter K., additional, Schneemann, Anette, additional, Schnellmann, Rick G., additional, Scholze, Henning, additional, Schomburg, Lutz, additional, Schwaeble, Wilhelm J., additional, Scott, Christopher J., additional, Scudiero, Rosaria, additional, Sehara-Fujisawa, Atsuko, additional, Seidah, Nabil G., additional, Seiki, Motoharu, additional, Sekiguchi, Junichi, additional, Senff-Ribeiro, Andrea, additional, Seong, Ihn Sik, additional, Serpe, Mihaela, additional, Serrano, Solange M.T., additional, Setlow, Peter, additional, Shahian, Tina, additional, Shanks, M., additional, Shao, Feng, additional, Shapiro, Steven D., additional, Sharma, Navneet, additional, Shaw, Lindsey N., additional, Shen, Aimee, additional, Shen, Lei, additional, Sherwood, Roger F., additional, Shi, Yun-Bo, additional, Shimoi, Hitoshi, additional, Shimura, Yoichiro, additional, Shirras, A.D., additional, Shridhar, Viji, additional, Shukla, Jinal K., additional, Siigur, Ene, additional, Siigur, Jüri, additional, Silmon de Monerri, Natalie C., additional, Sim, Robert B., additional, Simmer, James P., additional, Simmons, William H., additional, Singh, Jaspreet, additional, Singleton, Alison, additional, Sirakova, Tatiana D., additional, Sixma, Titia K., additional, Skern, Tim, additional, Skidgel, Randal A., additional, Slack, Jeffrey, additional, Sleat, David E., additional, Slusher, Barbara S., additional, Smith, Janet L., additional, Smith, Matthew A., additional, Smyth, Mark J., additional, Snijder, Erik J., additional, Sobhanifar, Solmaz, additional, Söderhaäll, Kenneth, additional, Sohar, Istvan, additional, Sonderegger, Peter, additional, Sorgine, Marcos Henrique Ferreira, additional, Sorimachi, Hiroyuki, additional, Soukhodolets, Karen E., additional, Souza, Tatiana de Arruda Campos Brasil de, additional, Sperka, Tamás, additional, Sriskandan, Shiranee, additional, St. Geme, Joseph W., additional, St. Leger, Raymond J., additional, Staib, Peter, additional, Steele, James L., additional, Stefansson, Bjarki, additional, Steinkühler, Christian, additional, Stenberg, Leisa M., additional, Stenflo, Johan, additional, Stennicke, Henning R., additional, Stepanov, Valentin M., additional, Stepnaya, Olga A., additional, Steven, Frank, additional, Stevens, Richard L., additional, Stevenson, Kenneth J., additional, St-Louis, Mathieu, additional, Stobart, Christopher C., additional, Stöcker, Walter, additional, Storer, Andrew C., additional, Sträter, Norbert, additional, Strauss, Ellen G., additional, Strauss, James H., additional, Stříšovský, Kvido, additional, Strynadka, Natalie C.J., additional, Sturrock, Edward D., additional, Su, Dan, additional, Su, Xiao-Dong, additional, Suárez-Rendueles, Paz, additional, Sulea, Traian, additional, Sundararajan, Venkatesh, additional, Suno, Ryoji, additional, Suzuki, Carolyn K., additional, Suzuki, Fumiaki, additional, Suzuki, Hideyuki, additional, Suzuki, Nobuhiro, additional, Swenson, Stephen, additional, Szabady, Rose L., additional, Szecsi, Pal Bela, additional, Szilágyi, Lászlo, additional, Taha, Muhamed-Kheir, additional, Takahashi, Eizo, additional, Takahashi, Kenji, additional, Takai, Toshiro, additional, Takeda, Atsushi, additional, Takeda, Soichi, additional, Tame, Jeremy J.R.H., additional, Tamura, Tomohiro, additional, Tan, Fulong, additional, Tanaka, Keiji, additional, Tanase, Carmen, additional, Tang, Jordan, additional, Tanizaki, Martha M., additional, Tannich, Egbert, additional, Tans, Guido, additional, Tarentino, Anthony L., additional, Tassanakajon, Anchalee, additional, Tatsumi, Hiroki, additional, Tautz, Norbert, additional, Taylor, Erin Bassford, additional, Teixeira, Pedro Filipe, additional, Telugu, Bhanu Prakash V.L., additional, Templin, Markus F., additional, Terada, Shigeyuki, additional, Tetsuya, Uchikoba, additional, Thacker, C., additional, Thaker, Maulik, additional, Thiel, Heinz-Jürgen, additional, Thielens, Nicole, additional, Thierry, Gonzales, additional, Thivierge, Karine, additional, Thomas, Mark D., additional, Thome, Margot, additional, Thorsness, Mary K., additional, Thorsness, Peter E., additional, Tigue, Natalie J., additional, Todi, Sokol V., additional, Tomkinson, Birgitta, additional, Tonello, Fiorella, additional, Tong, Liang, additional, Toogood, H.S., additional, Tortora, Paolo, additional, Tözsèr, József, additional, Travassos, Luiz Rodolpho, additional, Travis, James, additional, Trevisan-Silva, Dilza, additional, Trinchella, Francesca, additional, Trivedi, Neil N., additional, Troy, Carol M., additional, Tschesche, Harald, additional, Tseng, Yu-Lun, additional, Tsujimoto, Masafumi, additional, Tu, Anthony T., additional, Tumelty, Kathleen E., additional, Turk, Boris, additional, Turk, Dusan, additional, Turk, Vito, additional, Turner, Anthony J., additional, Uchikoba, Tetsuya, additional, Ueno, Takayuki, additional, Ugalde, Alejandro P., additional, Uitto, Veli-Jukka, additional, Urban, Sinisa, additional, Valdenaire, Olivier, additional, Valli, Adrian, additional, Van Beeumen, Jozef, additional, Van den Burg, Bertus, additional, Van der Hoorn, Renier A.L., additional, van Dijl, Jan Maarten, additional, Van Endert, Peter, additional, Van Raam, Bram J., additional, Van Wart, Harold E., additional, Vanden Berghe, Tom, additional, Vandenabeele, Peter, additional, Vanoni, Margo, additional, Veiga, Silvio Sanches, additional, Velander, William H., additional, Velasco, Gloria, additional, Vendrell, Josep, additional, Venekei, I. István, additional, Vetvicka, Vaclav, additional, Vögtle, F.-Nora, additional, Vollmer, Waldemar, additional, Wada, Kei, additional, Wagner, Fred W., additional, Wai, Sun Nyunt, additional, Wai, Timothy, additional, Wainwright, Shane, additional, Walker, Kenneth W., additional, Walker, Stephen J., additional, Wallach, Jean, additional, Walling, Linda L., additional, Walsh, Peter N., additional, Wang, Hai-Yan, additional, Wang, Hengbin, additional, Wang, Jianwei, additional, Wang, Peng, additional, Wang, Ping, additional, Wassenegger, Michael, additional, Watanabe, Kunihiko, additional, Webb, Helen, additional, Weber, Joseph M., additional, Weber, Niklas, additional, Webster, Daniel R., additional, Wei, Shuo, additional, Welch, Rodney A., additional, Wells, James A., additional, Wenzel, Herbert, additional, Wertz, Ingrid E., additional, Wewer, Ulla W., additional, Whyteside, Alison R., additional, Wilk, Sherwin, additional, Wilkin, Jean-Marc, additional, Wilmes, Claudia, additional, Winther, Jakob R., additional, Wishart, David S., additional, Wlodawer, Alexander, additional, Woessner, J. Fred, additional, Wolfe, Michael S., additional, Wong, Wilson, additional, Woodgate, Roger, additional, Wright, Gerry, additional, Wu, Jiunn-Jong, additional, Wu, Qingyu, additional, Wysocka, Magdalena, additional, Xu, Chao, additional, Xu, Zhenghong, additional, Yahori, Kinnosuke, additional, Yamada, Shoji, additional, Yamaguchi, Nozomi, additional, Yamaguchi, Shinji, additional, Yamakawa, Yoshio, additional, Yamamoto, Hiroki, additional, Yana, Ikao, additional, Yang, Maozhou, additional, Yang, Na, additional, Yao, Chenjuan, additional, Yao, Tingting, additional, Yasuda, Noriko, additional, Yasuhara, Toshimasa, additional, Yasumasu, Shigeki, additional, Yeh, Edward T.H., additional, Yiallouros, Irene, additional, Yin, Jiang, additional, Yonezawa, Hiroo, additional, Yoo, Soon Ji, additional, Yoshimoto, Tadashi, additional, Young, Michael W., additional, Young, Stephen G., additional, Zaidi, Nousheen, additional, Zavalova, Ludmila L., additional, Zavodszky, Peter, additional, Zhang, Aidong, additional, Zhang, Xianming, additional, Zhang, Yi-Zheng, additional, Zheng, Dominick, additional, Zhong, Guangming, additional, Zhong, Rong, additional, Zhou, Yuan, additional, Zhou, Zhaohui Sunny, additional, Zick, Michael, additional, Zigrino, Paola, additional, and Zimin, Andrei A., additional

Published
2013
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19. Pathogenic variants in PLOD3 result in a Stickler syndrome-like connective tissue disorder with vascular complications

Author

Ewans, LJ, Colley, A, Gaston-Massuet, C, Gualtieri, A, Cowley, MJ, McCabe, MJ, Anand, D, Lachke, SA, Scietti, L, Forneris, F, Zhu, Y, Ying, K, Walsh, C, Kirk, EP, Miller, D, Giunta, C, Sillence, D, DInger, M, Buckley, M, Roscioli, T, Ewans, LJ, Colley, A, Gaston-Massuet, C, Gualtieri, A, Cowley, MJ, McCabe, MJ, Anand, D, Lachke, SA, Scietti, L, Forneris, F, Zhu, Y, Ying, K, Walsh, C, Kirk, EP, Miller, D, Giunta, C, Sillence, D, DInger, M, Buckley, M, and Roscioli, T

Abstract

© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ. Background Pathogenic PLOD3 variants cause a connective tissue disorder (CTD) that has been described rarely. We further characterise this CTD and propose a clinical diagnostic label to improve recognition and diagnosis of PLOD3-related disease. Methods Reported PLOD3 phenotypes were compared with known CTDs utilising data from three further individuals from a consanguineous family with a homozygous PLOD3 c.809C>T; p.(Pro270Leu) variant. PLOD3 mRNA expression in the developing embryo was analysed for tissue-specific localisation. Mouse microarray expression data were assessed for phylogenetic gene expression similarities across CTDs with overlapping clinical features. Results Key clinical features included ocular abnormalities with risk for retinal detachment, sensorineural hearing loss, reduced palmar creases, finger contractures, prominent knees, scoliosis, low bone mineral density, recognisable craniofacial dysmorphisms, developmental delay and risk for vascular dissection. Collated clinical features showed most overlap with Stickler syndrome with variable features of Ehlers-Danlos syndrome (EDS) and epidermolysis bullosa (EB). Human lysyl hydroxylase 3/PLOD3 expression was localised to the developing cochlea, eyes, skin, forelimbs, heart and cartilage, mirroring the clinical phenotype of this disorder. Conclusion These data are consistent with pathogenic variants in PLOD3 resulting in a clinically distinct Stickler-like syndrome with vascular complications and variable features of EDS and EB. Early identification of PLOD3 variants would improve monitoring for comorbidities and may avoid serious adverse ocular and vascular outcomes.

Published
2019

26. Crystal Structure of full-length Human Lysyl Hydroxylase LH3

Author

Scietti, L., primary, Chiapparino, A., additional, De Giorgi, F., additional, Fumagalli, M., additional, Khoriauli, L., additional, Nergadze, S., additional, Basu, S., additional, Olieric, V., additional, Banushi, B., additional, Giulotto, E., additional, Gissen, P., additional, and Forneris, F., additional

Published
2018
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28. Crystal Structure of full-length Human Lysyl Hydroxylase LH3 - Cocrystal with Fe2+, Mn2+, UDP-Gal - Structure from long-wavelength S-SAD

Author

Scietti, L., primary, Chiapparino, A., additional, De Giorgi, F., additional, Fumagalli, M., additional, Khoriauli, L., additional, Nergadze, S., additional, Basu, S., additional, Olieric, V., additional, Banushi, B., additional, Giulotto, E., additional, Gissen, P., additional, and Forneris, F., additional

Published
2018
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29. Structure of Stem Cell Growth Factor R-spondin 1 in Complex with the Ectodomain of Its Receptor LGR5

Author

Peng, W.C., de Lau, W., Forneris, F., Granneman, J.C.M., Clevers, H.C., Gros, P., Crystal and Structural Chemistry, Sub Crystal and Structural Chemistry, Dep Biologie, and Hubrecht Institute for Developmental Biology and Stem Cell Research

Subjects
Models, Molecular, Gene Expression, Biology, Transfection, General Biochemistry, Genetics and Molecular Biology, Receptors, G-Protein-Coupled, 03 medical and health sciences, Structure-Activity Relationship, 0302 clinical medicine, Humans, Receptor, RSPO1, lcsh:QH301-705.5, 030304 developmental biology, 0303 health sciences, HEK 293 cells, Spondin 1, Wnt signaling pathway, LGR5, Cell biology, HEK293 Cells, Ectodomain, Biochemistry, lcsh:Biology (General), 030220 oncology & carcinogenesis, Intercellular Signaling Peptides and Proteins, Signal transduction, Thrombospondins, Signal Transduction
Abstract

SummaryLeucine-rich repeat-containing G protein-coupled receptors 4–6 (LGR4–LGR6) are receptors for R-spondins, potent Wnt agonists that exert profound trophic effects on Wnt-driven stem cells compartments. We present crystal structures of a signaling-competent fragment of R-spondin 1 (Rspo1) at a resolution of 2.0 Å and its complex with the LGR5 ectodomain at a resolution of 3.2 Å. Ecto-LGR5 binds Rspo1 at its concave leucine-rich-repeat (LRR) surface, forming a dimeric 2:2 complex. Fully conserved residues on LGR4–LGR6 explain promiscuous binding of R-spondins. A phenylalanine clamp formed by Rspo1 Phe106 and Phe110 pinches Ala190 of LGR5 and is critical for binding. Mutations related to congenital anonychia reduce signaling, but not binding of Rspo1 to LGR5. Furthermore, antibody binding to the extended loop of the C-terminal LRR cap of LGR5 activates signaling in a ligand-independent manner. Thus, our data reveal binding of R-spondins to conserved sites on LGR4–LGR6 and, in analogy to FSHR and related receptors, suggest a direct signaling role for LGR4–LGR6 in addition to its formation of Wnt receptor and coreceptor complexes.

Published
2013
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30. Assembly and Regulation of the Membrane Attack Complex Based on Structures of C5b6 and sC5b9

Author

Hadders, M.A., Bubeck, D., Roversi, P., Hakobyan, S., Forneris, F., Morgan, B.P., Pangburn, M.K., Llorca, O., Lea, S.M., Gros, P., Crystal and Structural Chemistry, Rontgen participation programme, Sub Crystal and Structural Chemistry, Crystal and Structural Chemistry, Rontgen participation programme, and Sub Crystal and Structural Chemistry

Subjects
Models, Molecular, C5b, Cryo-electron microscopy, Molecular Sequence Data, Complement, Complement C5b, Complement Membrane Attack Complex, Biology, Crystallography, X-Ray, Cleavage (embryo), Antibodies, Article, General Biochemistry, Genetics and Molecular Biology, Structure-Activity Relationship, 03 medical and health sciences, 0302 clinical medicine, Animals, Humans, Amino Acid Sequence, Lipid bilayer, lcsh:QH301-705.5, Peptide sequence, Membrane attack complex (MAC), X-ray crystallography, 030304 developmental biology, 0303 health sciences, MACPF, Sheep, Staining and Labeling, Cryoelectron Microscopy, Structure, Complement System Proteins, Cryo-electron microscopy (cryo-EM), 3. Good health, Cell biology, Complement system, Membrane, Solubility, lcsh:Biology (General), Complement membrane attack complex, 030217 neurology & neurosurgery
Abstract

8 páginas, 4 figuras, 4 figuras suplementarias -- 200-207, Activation of the complement system results in formation of membrane attack complexes (MACs), pores that disrupt lipid bilayers and lyse bacteria and other pathogens. Here, we present the crystal structure of the first assembly intermediate, C5b6, together with a cryo-electron microscopy reconstruction of a soluble, regulated form of the pore, sC5b9. Cleavage of C5 to C5b results in marked conformational changes, distinct from those observed in the homologous C3-to-C3b transition. C6 captures this conformation, which is preserved in the larger sC5b9 assembly. Together with antibody labeling, these structures reveal that complement components associate through sideways alignment of the central MAC-perforin (MACPF) domains, resulting in a C5b6-C7-C8b-C8a-C9 arc. Soluble regulatory proteins below the arc indicate a potential dual mechanism in protection from pore formation. These results provide a structural framework for understanding MAC pore formation and regulation, processes important for fighting infections and preventing complement-mediated tissue damage., This work was supported by Council for Chemical Sciences of the Netherlands Organization for Scientific Research (NWO-CW) grant 700.57.010, National Institutes of Health (NIH) grant 1 R01 AI072106-01A1; and European Research Council Advanced Grant 233229 to P.G.; Medical Research Council (MRC) grant G0400775 to S.M.L; Wellcome Trust Programme Grant 068590 to B.P.M.; Wellcome Trust Core Award Grant 090532/Z/09/Z; and a grant from the ‘‘Ramoón Areces’’ Foundation to O.L. O.L. is also supported by the Spanish Ministry of Science and Innovation (SAF2011-22988), ‘‘Red Temaática de Investigación Cooperativa en Cancer (RTICC), Instituto de Salud Carlos III’’ (RD06/0020/1001), Autonomous Region of Madrid (S2010-BMD-2316), and the Human Frontiers Science Program (RGP39/2008). D.B. is supported by EMBO. M.K.P. is supported by the NIH (grant RO1DK35081).

Published
2012
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31. Structures of C3b in Complex with Factors B and D Give Insight into Complement Convertase Formation

Author

Forneris, F., Ricklin, D., Wu, J., Tzekou, A., Wallace, R. S., Lambris, J.D., Gros, P., Crystal and Structural Chemistry, Sub Crystal and Structural Chemistry, Crystal and Structural Chemistry, and Sub Crystal and Structural Chemistry

Subjects
Models, Molecular, Protein Conformation, Complement Pathway, Alternative, Crystal structure, Biology, Crystallography, X-Ray, Complement factor B, Article, Catalytic Domain, Hydrolase, Humans, Complement C3 Convertase, Alternative Pathway, Binding Sites, Multidisciplinary, Substrate (chemistry), Protein Structure, Tertiary, Complement system, Complement (complexity), A-site, Crystallography, Complement C3b, biology.protein, Biophysics, Complement Factor D, Mutant Proteins, Factor D, Complement Factor B, Protein Binding
Abstract

A Safety Catch on Immune Response The complement system is an integral part of the innate immune system. When triggered, it initiates a cascade that marks intruders for elimination and stimulates immune responses. The key amplification step is cleavage of a complex comprising the complement fragment C3b and factor B (C3bB) by factor D (FD). Forneris et al. (p. 1816 ) now describe the crystal structure of C3bB and its complex with FD. The structures support a mechanism in which membrane-bound C3b stabilizes an open form of factor B (FB) that has its scissile bond accessible. FD binds through a site distant from its catalytic center to the open form of FB, which activates FD. The two conformational equilibria represent a double safety-catch that would allow tight regulation of this immune response pathway.

Published
2010
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35. A highly specific mechanism of histone H3-K4 recognition by histone demethylase LSD1

Author

Forneris, F., Binda, C., Dall'Aglio, A., Fraaije, M.W., Battaglioli, E., Mattevi, A., Aglio, Annachiara Dall’, Biotechnologie, Faculty of Science and Engineering, and Groningen Biomolecular Sciences and Biotechnology

Subjects
CHROMATIN, Transcription, Genetic, CODE, Biology, OXIDASE, Biochemistry, Cell Line, Substrate Specificity, Histones, Histone H3, Histone methylation, Histone H2A, Humans, ARGININE METHYLATION, Histone octamer, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Molecular Biology, Histone Demethylases, Histone deacetylase 5, Histone deacetylase 2, Oxidoreductases, N-Demethylating, Cell Biology, H3K4ME3, Oxygen, Histone methyltransferase, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, ENZYMES
Abstract

Human lysine-specific demethylase (LSD1) is a chromatin-modifying enzyme that specifically removes methyl groups from mono- and dimethylated Lys4 of histone H3 (H3-K4). We used a combination of in vivo and in vitro experiments to characterize the substrate specificity and recognition by LSD1. Biochemical assays on histone peptides show that essentially all epigenetic modifications on the 21 N-terminal amino acids of histone H3 cause a significant reduction in enzymatic activity. Replacement of Lys4 with Arg greatly enhances binding affinity, and a histone peptide incorporating this mutation has a strong inhibitory power. Conversely, a peptide bearing a trimethylated Lys4 is only a weak inhibitor of the enzyme. Rapid kinetics measurements evidence that the enzyme is efficiently reoxidized by molecular oxygen with a second-order rate constant of 9.6x10(3) M-1 s-1, and that the presence of the reaction product does not greatly influence the rate of flavin reoxidation. In vivo experiments provide a correlation between the in vitro inhibitory properties of the tested peptides and their ability of affecting endogenous LSD1 activity. Our results show that epigenetic modifications on histone H3 need to be removed before Lys4 demethylation can efficiently occur. The complex formed by LSD1 with histone deacetylases 1/2 may function as a "double-blade razor" that first eliminates the acetyl groups from acetylated Lys residues and then removes the methyl group from Lys4. We suggest that after H3-K4 demethylation, LSD1 recruits the forthcoming chromatin remodelers leading to the introduction of gene repression marks.

Published
2006
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36. Structural and biochemical evaluation of Ceratitiscapitata odorant‐binding protein 22 affinity for odorants involved in intersex communication.

Author

Falchetto, M., Ciossani, G., Scolari, F., Di Cosimo, A., Nenci, S., Field, L. M., Mattevi, A., Zhou, J.‐J., Gasperi, G., and Forneris, F.

Subjects
OLFACTORY receptors, MEDITERRANEAN fruit-fly, SENSORY receptors, DROSOPHILA melanogaster, ELECTRON density, HYDROPHOBIC compounds, ODORANT-binding proteins
Abstract

In insects, odorant‐binding proteins (OBPs) connect the peripheral sensory system to receptors of olfactory organs. Medfly Ceratitis capitata CcapObp22 shows 37% identity and close phylogenetic affinities with Drosophila melanogaster OBP69a/pheromone‐binding protein related protein 1. The CcapObp22 gene is transcribed in the antennae and maxillary palps, suggesting an active role in olfaction. Here, we recombinantly produced CcapObp22, obtaining a 13.5 kDa protein capable of binding multiple strongly hydrophobic terpene compounds, including medfly male pheromone components. The highest binding affinity [half maximal effective concentration (EC50) = 0.48 µM] was to (E,E)‐α‐farnesene, one of the most abundant compounds in the male pheromone blend. This odorant was used in cocrystallization experiments, yielding the structure of CcapOBP22. The monomeric structure shows the typical OBP folding, constituted by six α‐helical elements interconnected by three disulphide bridges. A C‐terminal seventh α‐helix constitutes the wall of a deep, L‐shaped hydrophobic cavity. Analysis of the electron density in this cavity suggested trapping of farnesene in the crystal structure, although with partial occupancy. Superposition of the CcapOBP22 structure with related seven‐helical OBPs highlights striking similarity in the organization of the C‐terminal segment of these proteins. Collectively, our molecular and physiological data on medfly CcapOBP22 suggest its involvement in intersex olfactory communication. [ABSTRACT FROM AUTHOR]

Published
2019
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37. Regulators of complement activity mediate inhibitory mechanisms through a common C3b-binding mode

Author

Forneris, F., Wu, J., Xue, X., Ricklin, D., Lin, Z., Sfyroera, G., Tzekou, A., Volokhina, E.B., Granneman, J.C., Hauhart, R., Bertram, P., Liszewski, M.K., Atkinson, J.P., Lambris, J.D., Gros, P., Forneris, F., Wu, J., Xue, X., Ricklin, D., Lin, Z., Sfyroera, G., Tzekou, A., Volokhina, E.B., Granneman, J.C., Hauhart, R., Bertram, P., Liszewski, M.K., Atkinson, J.P., Lambris, J.D., and Gros, P.

Abstract

Item does not contain fulltext

Published
2016

38. LSD1-CoREST1 in complex with polymyxin E (colistin)

Author

Speranzini, V., primary, Rotili, D., additional, Ciossani, G., additional, Pilotto, S., additional, Forgione, M., additional, Lucidi, A., additional, Forneris, F., additional, Velankar, S., additional, Mai, A., additional, and Mattevi, A., additional

Published
2016
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40. LSD1-CoREST1 in complex with polymyxin B

Author

Speranzini, V., primary, Rotili, D., additional, Ciossani, G., additional, Pilotto, S., additional, Forgione, M., additional, Lucidi, A., additional, Forneris, F., additional, Velankar, S., additional, Mai, A., additional, and Mattevi, A., additional

Published
2016
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48. Structures of Wnt-antagonist ZNRF3 and its complex with R-spondin 1 and implications for signaling

Author

Peng, W.C., de Lau, W., Madoori, P.K., Forneris, F., Granneman, J.C.M., Clevers, H., Gros, P., Crystal and Structural Chemistry, Sub Crystal and Structural Chemistry, Dep Biologie, Crystal and Structural Chemistry, Sub Crystal and Structural Chemistry, Dep Biologie, and Hubrecht Institute for Developmental Biology and Stem Cell Research

Subjects
Frizzled, Science, Ubiquitin-Protein Ligases, Biology, Crystallography, X-Ray, Receptors, G-Protein-Coupled, 03 medical and health sciences, Mice, 0302 clinical medicine, Ring finger, medicine, Animals, Humans, RSPO1, Protein Structure, Quaternary, Wnt Signaling Pathway, 030304 developmental biology, Oncogene Proteins, 0303 health sciences, Multidisciplinary, Spondin 1, Wnt signaling pathway, LRP6, LRP5, Cell biology, DNA-Binding Proteins, Adult Stem Cells, medicine.anatomical_structure, HEK293 Cells, Ectodomain, 030220 oncology & carcinogenesis, Multiprotein Complexes, Medicine, Thrombospondins, Research Article
Abstract

Zinc RING finger 3 (ZNRF3) and its homolog RING finger 43 (RNF43) antagonize Wnt signaling in adult stem cells by ubiquitinating Frizzled receptors (FZD), which leads to endocytosis of the Wnt receptor. Conversely, binding of ZNRF3/RNF43 to LGR4-6 – R-spondin blocks Frizzled ubiquitination and enhances Wnt signaling. Here, we present crystal structures of the ZNRF3 ectodomain and its complex with R-spondin 1 (RSPO1). ZNRF3 binds RSPO1 and LGR5-RSPO1 with micromolar affinity via RSPO1 furin-like 1 (Fu1) domain. Anonychia-related mutations in RSPO4 support the importance of the observed interface. The ZNRF3-RSPO1 structure resembles that of LGR5-RSPO1- RNF43, though Fu2 of RSPO1 is variably oriented. The ZNRF3-binding site overlaps with trans-interactions observed in 2:2 LGR5-RSPO1 complexes, thus binding of ZNRF3/RNF43 would disrupt such an arrangement. Sequence conservation suggests a single ligand-binding site on ZNRF3, consistent with the proposed competing binding role of ZNRF3/RNF43 in Wnt signaling.

Published
2013
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49. The modular serine proteases of the complement cascade

Author

Forneris, F., Wu, J., Gros, P., Crystal and Structural Chemistry, Rontgen participation programme, Sub Crystal and Structural Chemistry, Crystal and Structural Chemistry, Rontgen participation programme, and Sub Crystal and Structural Chemistry

Subjects
Models, Molecular, Proteases, Protein Conformation, Complement receptor, Complement C3-C5 Convertases, Biology, Models, Biological, C5-convertase, Serine, 03 medical and health sciences, 0302 clinical medicine, Immune system, Structural Biology, Animals, Humans, Molecular Biology, Complement Activation, 030304 developmental biology, 0303 health sciences, Complement component 2, Complement System Proteins, C3-convertase, 3. Good health, Complement system, Enzyme Activation, Biochemistry, Serine Proteases, 030215 immunology
Abstract

Modular serine proteases are central to the complement cascade of the mammalian humoral immune system. These proteases form protein complexes through multi-domain interactions to achieve their proteolytic activity. We review the structural insights into complement initiation by auto-activation of the hetero-tetrameric proteases of the large danger-recognition protein complexes, amplification and labelling of particles by the formation and activity of C3 convertases, and regulation by convertase dissociation and degradation to prevent ‘bystander’ damage to healthy host cells and tissues. The data reveal that complex formation and large domain–domain rearrangements underlie the proteolytic reactions of the complement cascade, which enables the host to recognize and clear invading microbes and host debris from its blood and fluids surrounding tissues.

Published
2012

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