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1. Correction to “The thymocyte-specific RNA-binding protein Arpp21 provides TCR repertoire diversity by binding to the 3’-UTR and promoting Rag1 mRNA expression”

Author

Xu, Meng, Ito-Kureha, Taku, Kang, Hyun-Seo, Chernev, Aleksandar, Raj, Timsse, Hoefig, Kai P., Hohn, Christine, Giesert, Florian, Wang, Yinhu, Pan, Wenliang, Ziętara, Natalia, Straub, Tobias, Feederle, Regina, Daniel, Carolin, Adler, Barbara, König, Julian, Feske, Stefan, Tsokos, George C., Wurst, Wolfgang, Urlaub, Henning, Sattler, Michael, Kisielow, Jan, Wulczyn, F. Gregory, Łyszkiewicz, Marcin, and Heissmeyer, Vigo

Published
2024
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4. The thymocyte-specific RNA-binding protein Arpp21 provides TCR repertoire diversity by binding to the 3’-UTR and promoting Rag1 mRNA expression

Author

Xu, Meng, Ito-Kureha, Taku, Kang, Hyun-Seo, Chernev, Aleksandar, Raj, Timsse, Hoefig, Kai P., Hohn, Christine, Giesert, Florian, Wang, Yinhu, Pan, Wenliang, Ziętara, Natalia, Straub, Tobias, Feederle, Regina, Daniel, Carolin, Adler, Barbara, König, Julian, Feske, Stefan, Tsokos, George C., Wurst, Wolfgang, Urlaub, Henning, Sattler, Michael, Kisielow, Jan, Wulczyn, F. Gregory, Łyszkiewicz, Marcin, and Heissmeyer, Vigo

Published
2024
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7. Urbanisation generates multiple trait syndromes for terrestrial animal taxa worldwide.

Author

Hahs, Amy, Fournier, Bertrand, Aronson, Myla, Nilon, Charles, Herrera-Montes, Adriana, Salisbury, Allyson, Threlfall, Caragh, Rega-Brodsky, Christine, Lepczyk, Christopher, La Sorte, Frank, MacGregor-Fors, Ian, Scott MacIvor, J, Jung, Kirsten, Piana, Max, Williams, Nicholas, Knapp, Sonja, Vergnes, Alan, Acevedo, Aldemar, Gainsbury, Alison, Rainho, Ana, Hamer, Andrew, Shwartz, Assaf, Voigt, Christian, Lewanzik, Daniel, Lowenstein, David, OBrien, David, Tommasi, Desiree, Pineda, Eduardo, Carpenter, Ela, Belskaya, Elena, Lövei, Gábor, Makinson, James, Coleman, Joanna, Sadler, Jon, Shroyer, Jordan, Shapiro, Julie, Baldock, Katherine, Ksiazek-Mikenas, Kelly, Matteson, Kevin, Barrett, Kyle, Siles, Lizette, Aguirre, Luis, Armesto, Luis, Zalewski, Marcin, Herrera-Montes, Maria, Obrist, Martin, Tonietto, Rebecca, Gagné, Sara, Hinners, Sarah, Latty, Tanya, Surasinghe, Thilina, Sattler, Thomas, Magura, Tibor, Ulrich, Werner, Elek, Zoltan, Castañeda-Oviedo, Jennifer, Torrado, Ricardo, Kotze, D, and Moretti, Marco

Subjects
Animals, Bees, Urbanization, Syndrome, Ecosystem, Biodiversity, Birds, Chiroptera
Abstract

Cities can host significant biological diversity. Yet, urbanisation leads to the loss of habitats, species, and functional groups. Understanding how multiple taxa respond to urbanisation globally is essential to promote and conserve biodiversity in cities. Using a dataset encompassing six terrestrial faunal taxa (amphibians, bats, bees, birds, carabid beetles and reptiles) across 379 cities on 6 continents, we show that urbanisation produces taxon-specific changes in trait composition, with traits related to reproductive strategy showing the strongest response. Our findings suggest that urbanisation results in four trait syndromes (mobile generalists, site specialists, central place foragers, and mobile specialists), with resources associated with reproduction and diet likely driving patterns in traits associated with mobility and body size. Functional diversity measures showed varied responses, leading to shifts in trait space likely driven by critical resource distribution and abundance, and taxon-specific trait syndromes. Maximising opportunities to support taxa with different urban trait syndromes should be pivotal in conservation and management programmes within and among cities. This will reduce the likelihood of biotic homogenisation and helps ensure that urban environments have the capacity to respond to future challenges. These actions are critical to reframe the role of cities in global biodiversity loss.

Published
2023

8. Correction to 'The thymocyte-specific RNA-binding protein Arpp21 provides TCR repertoire diversity by binding to the 3’-UTR and promoting Rag1 mRNA expression'

Author

Meng Xu, Taku Ito-Kureha, Hyun-Seo Kang, Aleksandar Chernev, Timsse Raj, Kai P. Hoefig, Christine Hohn, Florian Giesert, Yinhu Wang, Wenliang Pan, Natalia Ziętara, Tobias Straub, Regina Feederle, Carolin Daniel, Barbara Adler, Julian König, Stefan Feske, George C. Tsokos, Wolfgang Wurst, Henning Urlaub, Michael Sattler, Jan Kisielow, F. Gregory Wulczyn, Marcin Łyszkiewicz, and Vigo Heissmeyer

Subjects
Science
Published
2024
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9. Intramolecular autoinhibition regulates the selectivity of PRPF40A tandem WW domains for proline-rich motifs

Author

Santiago Martínez-Lumbreras, Lena K. Träger, Miriam M. Mulorz, Marco Payr, Varvara Dikaya, Clara Hipp, Julian König, and Michael Sattler

Subjects
Science
Abstract

Abstract PRPF40A plays an important role in the regulation of pre-mRNA splicing by mediating protein-protein interactions in the early steps of spliceosome assembly. By binding to proteins at the 5´ and 3´ splice sites, PRPF40A promotes spliceosome assembly by bridging the recognition of the splices. The PRPF40A WW domains are expected to recognize proline-rich sequences in SF1 and SF3A1 in the early spliceosome complexes E and A, respectively. Here, we combine NMR, SAXS and ITC to determine the structure of the PRPF40A tandem WW domains in solution and characterize the binding specificity and mechanism for proline-rich motifs recognition. Our structure of the PRPF40A WW tandem in complex with a high-affinity SF1 peptide reveals contributions of both WW domains, which also enables tryptophan sandwiching by two proline residues in the ligand. Unexpectedly, a proline-rich motif in the N-terminal region of PRPF40A mediates intramolecular interactions with the WW tandem. Using NMR, ITC, mutational analysis in vitro, and immunoprecipitation experiments in cells, we show that the intramolecular interaction acts as an autoinhibitory filter for proof-reading of high-affinity proline-rich motifs in bona fide PRPF40A binding partners. We propose that similar autoinhibitory mechanisms are present in most WW tandem-containing proteins to enhance binding selectivity and regulation of WW/proline-rich peptide interaction networks.

Published
2024
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10. Modulation of peroxisomal import by the PEX13 SH3 domain and a proximal FxxxF binding motif

Author

Stefan Gaussmann, Rebecca Peschel, Julia Ott, Krzysztof M. Zak, Judit Sastre, Florent Delhommel, Grzegorz M. Popowicz, Job Boekhoven, Wolfgang Schliebs, Ralf Erdmann, and Michael Sattler

Subjects
Science
Abstract

Abstract Import of proteins into peroxisomes depends on PEX5, PEX13 and PEX14. By combining biochemical methods and structural biology, we show that the C-terminal SH3 domain of PEX13 mediates intramolecular interactions with a proximal FxxxF motif. The SH3 domain also binds WxxxF peptide motifs in the import receptor PEX5, demonstrating evolutionary conservation of such interactions from yeast to human. Strikingly, intramolecular interaction of the PEX13 FxxxF motif regulates binding of PEX5 WxxxF/Y motifs to the PEX13 SH3 domain. Crystal structures reveal how FxxxF and WxxxF/Y motifs are recognized by a non-canonical surface on the SH3 domain. The PEX13 FxxxF motif also mediates binding to PEX14. Surprisingly, the potential PxxP binding surface of the SH3 domain does not recognize PEX14 PxxP motifs, distinct from its yeast ortholog. Our data show that the dynamic network of PEX13 interactions with PEX5 and PEX14, mediated by diaromatic peptide motifs, modulates peroxisomal matrix import.

Published
2024
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11. The thymocyte-specific RNA-binding protein Arpp21 provides TCR repertoire diversity by binding to the 3’-UTR and promoting Rag1 mRNA expression

Author

Meng Xu, Taku Ito-Kureha, Hyun-Seo Kang, Aleksandar Chernev, Timsse Raj, Kai P. Hoefig, Christine Hohn, Florian Giesert, Yinhu Wang, Wenliang Pan, Natalia Ziętara, Tobias Straub, Regina Feederle, Carolin Daniel, Barbara Adler, Julian König, Stefan Feske, George C. Tsokos, Wolfgang Wurst, Henning Urlaub, Michael Sattler, Jan Kisielow, F. Gregory Wulczyn, Marcin Łyszkiewicz, and Vigo Heissmeyer

Subjects
Science
Abstract

Abstract The regulation of thymocyte development by RNA-binding proteins (RBPs) is largely unexplored. We identify 642 RBPs in the thymus and focus on Arpp21, which shows selective and dynamic expression in early thymocytes. Arpp21 is downregulated in response to T cell receptor (TCR) and Ca2+ signals. Downregulation requires Stim1/Stim2 and CaMK4 expression and involves Arpp21 protein phosphorylation, polyubiquitination and proteasomal degradation. Arpp21 directly binds RNA through its R3H domain, with a preference for uridine-rich motifs, promoting the expression of target mRNAs. Analysis of the Arpp21–bound transcriptome reveals strong interactions with the Rag1 3′-UTR. Arpp21–deficient thymocytes show reduced Rag1 expression, delayed TCR rearrangement and a less diverse TCR repertoire. This phenotype is recapitulated in Rag1 3′-UTR mutant mice harboring a deletion of the Arpp21 response region. These findings show how thymocyte-specific Arpp21 promotes Rag1 expression to enable TCR repertoire diversity until signals from the TCR terminate Arpp21 and Rag1 activities.

Published
2024
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12. YTHDF2 governs muscle size through a targeted modulation of proteostasis

Author

Christopher J. Gilbert, Charles P. Rabolli, Volha A. Golubeva, Kristina M. Sattler, Meifang Wang, Arsh Ketabforoush, W. David Arnold, Christoph Lepper, and Federica Accornero

Subjects
Science
Abstract

Abstract The regulation of proteostasis is fundamental for maintenance of muscle mass and function. Activation of the TGF-β pathway drives wasting and premature aging by favoring the proteasomal degradation of structural muscle proteins. Yet, how this critical post-translational mechanism is kept in check to preserve muscle health remains unclear. Here, we reveal the molecular link between the post-transcriptional regulation of m6A-modified mRNA and the modulation of SMAD-dependent TGF-β signaling. We show that the m6A-binding protein YTHDF2 is essential to determining postnatal muscle size. Indeed, muscle-specific genetic deletion of YTHDF2 impairs skeletal muscle growth and abrogates the response to hypertrophic stimuli. We report that YTHDF2 controls the mRNA stability of the ubiquitin ligase ASB2 with consequences on anti-growth gene program activation through SMAD3. Our study identifies a post-transcriptional to post-translational mechanism for the coordination of gene expression in muscle.

Published
2024
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13. Warming underpins community turnover in temperate freshwater and terrestrial communities

Author

Imran Khaliq, Christian Rixen, Florian Zellweger, Catherine H. Graham, Martin M. Gossner, Ian R. McFadden, Laura Antão, Jakob Brodersen, Shyamolina Ghosh, Francesco Pomati, Ole Seehausen, Tobias Roth, Thomas Sattler, Sarah R. Supp, Maria Riaz, Niklaus E. Zimmermann, Blake Matthews, and Anita Narwani

Subjects
Science
Abstract

Abstract Rising temperatures are leading to increased prevalence of warm-affinity species in ecosystems, known as thermophilisation. However, factors influencing variation in thermophilisation rates among taxa and ecosystems, particularly freshwater communities with high diversity and high population decline, remain unclear. We analysed compositional change over time in 7123 freshwater and 6201 terrestrial, mostly temperate communities from multiple taxonomic groups. Overall, temperature change was positively linked to thermophilisation in both realms. Extirpated species had lower thermal affinities in terrestrial communities but higher affinities in freshwater communities compared to those persisting over time. Temperature change’s impact on thermophilisation varied with community body size, thermal niche breadth, species richness and baseline temperature; these interactive effects were idiosyncratic in the direction and magnitude of their impacts on thermophilisation, both across realms and taxonomic groups. While our findings emphasise the challenges in predicting the consequences of temperature change across communities, conservation strategies should consider these variable responses when attempting to mitigate climate-induced biodiversity loss.

Published
2024
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14. Pharmacological perturbation of the phase-separating protein SMNDC1

Author

Enders, Lennart, Siklos, Marton, Borggräfe, Jan, Gaussmann, Stefan, Koren, Anna, Malik, Monika, Tomek, Tatjana, Schuster, Michael, Reiniš, Jiří, Hahn, Elisa, Rukavina, Andrea, Reicher, Andreas, Casteels, Tamara, Bock, Christoph, Winter, Georg E., Hannich, J. Thomas, Sattler, Michael, and Kubicek, Stefan

Published
2023
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15. Local colonisations and extinctions of European birds are poorly explained by changes in climate suitability

Author

Howard, Christine, Marjakangas, Emma-Liina, Morán-Ordóñez, Alejandra, Milanesi, Pietro, Abuladze, Aleksandre, Aghababyan, Karen, Ajder, Vitalie, Arkumarev, Volen, Balmer, Dawn E., Bauer, Hans-Günther, Beale, Colin M., Bino, Taulant, Boyla, Kerem Ali, Burfield, Ian J., Burke, Brian, Caffrey, Brian, Chodkiewicz, Tomasz, Del Moral, Juan Carlos, Mazal, Vlatka Dumbovic, Fernández, Néstor, Fornasari, Lorenzo, Gerlach, Bettina, Godinho, Carlos, Herrando, Sergi, Ieronymidou, Christina, Johnston, Alison, Jovicevic, Mihailo, Kalyakin, Mikhail, Keller, Verena, Knaus, Peter, Kotrošan, Dražen, Kuzmenko, Tatiana, Leitão, Domingos, Lindström, Åke, Maxhuni, Qenan, Mihelič, Tomaž, Mikuska, Tibor, Molina, Blas, Nagy, Károly, Noble, David, Øien, Ingar Jostein, Paquet, Jean-Yves, Pladevall, Clara, Portolou, Danae, Radišić, Dimitrije, Rajkov, Saša, Rajković, Draženko Z., Raudonikis, Liutauras, Sattler, Thomas, Saveljić, Darko, Shimmings, Paul, Sjenicic, Jovica, Šťastný, Karel, Stoychev, Stoycho, Strus, Iurii, Sudfeldt, Christoph, Sultanov, Elchin, Szép, Tibor, Teufelbauer, Norbert, Uzunova, Danka, van Turnhout, Chris A. M., Velevski, Metodija, Vikstrøm, Thomas, Vintchevski, Alexandre, Voltzit, Olga, Voříšek, Petr, Wilk, Tomasz, Zurell, Damaris, Brotons, Lluís, Lehikoinen, Aleksi, and Willis, Stephen G.

Published
2023
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17. Pharmacological perturbation of the phase-separating protein SMNDC1

Author

Lennart Enders, Marton Siklos, Jan Borggräfe, Stefan Gaussmann, Anna Koren, Monika Malik, Tatjana Tomek, Michael Schuster, Jiří Reiniš, Elisa Hahn, Andrea Rukavina, Andreas Reicher, Tamara Casteels, Christoph Bock, Georg E. Winter, J. Thomas Hannich, Michael Sattler, and Stefan Kubicek

Subjects
Science
Abstract

Abstract SMNDC1 is a Tudor domain protein that recognizes di-methylated arginines and controls gene expression as an essential splicing factor. Here, we study the specific contributions of the SMNDC1 Tudor domain to protein-protein interactions, subcellular localization, and molecular function. To perturb the protein function in cells, we develop small molecule inhibitors targeting the dimethylarginine binding pocket of the SMNDC1 Tudor domain. We find that SMNDC1 localizes to phase-separated membraneless organelles that partially overlap with nuclear speckles. This condensation behavior is driven by the unstructured C-terminal region of SMNDC1, depends on RNA interaction and can be recapitulated in vitro. Inhibitors of the protein’s Tudor domain drastically alter protein-protein interactions and subcellular localization, causing splicing changes for SMNDC1-dependent genes. These compounds will enable further pharmacological studies on the role of SMNDC1 in the regulation of nuclear condensates, gene regulation and cell identity.

Published
2023
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18. Urbanisation generates multiple trait syndromes for terrestrial animal taxa worldwide

Author

Amy K. Hahs, Bertrand Fournier, Myla F. J. Aronson, Charles H. Nilon, Adriana Herrera-Montes, Allyson B. Salisbury, Caragh G. Threlfall, Christine C. Rega-Brodsky, Christopher A. Lepczyk, Frank A. La Sorte, Ian MacGregor-Fors, J. Scott MacIvor, Kirsten Jung, Max R. Piana, Nicholas S. G. Williams, Sonja Knapp, Alan Vergnes, Aldemar A. Acevedo, Alison M. Gainsbury, Ana Rainho, Andrew J. Hamer, Assaf Shwartz, Christian C. Voigt, Daniel Lewanzik, David M. Lowenstein, David O’Brien, Desiree Tommasi, Eduardo Pineda, Ela Sita Carpenter, Elena Belskaya, Gábor L. Lövei, James C. Makinson, Joanna L. Coleman, Jon P. Sadler, Jordan Shroyer, Julie Teresa Shapiro, Katherine C. R. Baldock, Kelly Ksiazek-Mikenas, Kevin C. Matteson, Kyle Barrett, Lizette Siles, Luis F. Aguirre, Luis Orlando Armesto, Marcin Zalewski, Maria Isabel Herrera-Montes, Martin K. Obrist, Rebecca K. Tonietto, Sara A. Gagné, Sarah J. Hinners, Tanya Latty, Thilina D. Surasinghe, Thomas Sattler, Tibor Magura, Werner Ulrich, Zoltan Elek, Jennifer Castañeda-Oviedo, Ricardo Torrado, D. Johan Kotze, and Marco Moretti

Subjects
Science
Abstract

Abstract Cities can host significant biological diversity. Yet, urbanisation leads to the loss of habitats, species, and functional groups. Understanding how multiple taxa respond to urbanisation globally is essential to promote and conserve biodiversity in cities. Using a dataset encompassing six terrestrial faunal taxa (amphibians, bats, bees, birds, carabid beetles and reptiles) across 379 cities on 6 continents, we show that urbanisation produces taxon-specific changes in trait composition, with traits related to reproductive strategy showing the strongest response. Our findings suggest that urbanisation results in four trait syndromes (mobile generalists, site specialists, central place foragers, and mobile specialists), with resources associated with reproduction and diet likely driving patterns in traits associated with mobility and body size. Functional diversity measures showed varied responses, leading to shifts in trait space likely driven by critical resource distribution and abundance, and taxon-specific trait syndromes. Maximising opportunities to support taxa with different urban trait syndromes should be pivotal in conservation and management programmes within and among cities. This will reduce the likelihood of biotic homogenisation and helps ensure that urban environments have the capacity to respond to future challenges. These actions are critical to reframe the role of cities in global biodiversity loss.

Published
2023
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19. Local colonisations and extinctions of European birds are poorly explained by changes in climate suitability

Author

Christine Howard, Emma-Liina Marjakangas, Alejandra Morán-Ordóñez, Pietro Milanesi, Aleksandre Abuladze, Karen Aghababyan, Vitalie Ajder, Volen Arkumarev, Dawn E. Balmer, Hans-Günther Bauer, Colin M. Beale, Taulant Bino, Kerem Ali Boyla, Ian J. Burfield, Brian Burke, Brian Caffrey, Tomasz Chodkiewicz, Juan Carlos Del Moral, Vlatka Dumbovic Mazal, Néstor Fernández, Lorenzo Fornasari, Bettina Gerlach, Carlos Godinho, Sergi Herrando, Christina Ieronymidou, Alison Johnston, Mihailo Jovicevic, Mikhail Kalyakin, Verena Keller, Peter Knaus, Dražen Kotrošan, Tatiana Kuzmenko, Domingos Leitão, Åke Lindström, Qenan Maxhuni, Tomaž Mihelič, Tibor Mikuska, Blas Molina, Károly Nagy, David Noble, Ingar Jostein Øien, Jean-Yves Paquet, Clara Pladevall, Danae Portolou, Dimitrije Radišić, Saša Rajkov, Draženko Z. Rajković, Liutauras Raudonikis, Thomas Sattler, Darko Saveljić, Paul Shimmings, Jovica Sjenicic, Karel Šťastný, Stoycho Stoychev, Iurii Strus, Christoph Sudfeldt, Elchin Sultanov, Tibor Szép, Norbert Teufelbauer, Danka Uzunova, Chris A. M. van Turnhout, Metodija Velevski, Thomas Vikstrøm, Alexandre Vintchevski, Olga Voltzit, Petr Voříšek, Tomasz Wilk, Damaris Zurell, Lluís Brotons, Aleksi Lehikoinen, and Stephen G. Willis

Subjects
Science
Abstract

Abstract Climate change has been associated with both latitudinal and elevational shifts in species’ ranges. The extent, however, to which climate change has driven recent range shifts alongside other putative drivers remains uncertain. Here, we use the changing distributions of 378 European breeding bird species over 30 years to explore the putative drivers of recent range dynamics, considering the effects of climate, land cover, other environmental variables, and species’ traits on the probability of local colonisation and extinction. On average, species shifted their ranges by 2.4 km/year. These shifts, however, were significantly different from expectations due to changing climate and land cover. We found that local colonisation and extinction events were influenced primarily by initial climate conditions and by species’ range traits. By contrast, changes in climate suitability over the period were less important. This highlights the limitations of using only climate and land cover when projecting future changes in species’ ranges and emphasises the need for integrative, multi-predictor approaches for more robust forecasting.

Published
2023
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20. Structural basis for specific RNA recognition by the alternative splicing factor RBM5

Author

Komal Soni, Pravin Kumar Ankush Jagtap, Santiago Martínez-Lumbreras, Sophie Bonnal, Arie Geerlof, Ralf Stehle, Bernd Simon, Juan Valcárcel, and Michael Sattler

Subjects
Science
Abstract

Abstract The RNA-binding motif protein RBM5 belongs to a family of multi-domain RNA binding proteins that regulate alternative splicing of genes important for apoptosis and cell proliferation and have been implicated in cancer. RBM5 harbors structural modules for RNA recognition, such as RRM domains and a Zn finger, and protein-protein interactions such as an OCRE domain. Here, we characterize binding of the RBM5 RRM1-ZnF1-RRM2 domains to cis-regulatory RNA elements. A structure of the RRM1-ZnF1 region in complex with RNA shows how the tandem domains cooperate to sandwich target RNA and specifically recognize a GG dinucleotide in a non-canonical fashion. While the RRM1-ZnF1 domains act as a single structural module, RRM2 is connected by a flexible linker and tumbles independently. However, all three domains participate in RNA binding and adopt a closed architecture upon RNA binding. Our data highlight how cooperativity and conformational modularity of multiple RNA binding domains enable the recognition of distinct RNA motifs, thereby contributing to the regulation of alternative splicing. Remarkably, we observe surprising differences in coupling of the RNA binding domains between the closely related homologs RBM5 and RBM10.

Published
2023
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21. Genetic analysis of seed traits in Sorghum bicolor that affect the human gut microbiome

Author

Qinnan Yang, Mallory Van Haute, Nate Korth, Scott E. Sattler, John Toy, Devin J. Rose, James C. Schnable, and Andrew K. Benson

Subjects
Science
Abstract

Diet affects the human gut microbiome, but studies linking crop genetics to seed traits that influence the human gut microbiome are lacking. Here, the authors develop an in vitro microbiome screening method and reveal the association between sorghum genes regulating condensed tannin biosynthesis and human gut microbiome.

Published
2022
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24. Active coacervate droplets as a model for membraneless organelles and protocells

Author

Carsten Donau, Fabian Späth, Marilyne Sosson, Brigitte A. K. Kriebisch, Fabian Schnitter, Marta Tena-Solsona, Hyun-Seo Kang, Elia Salibi, Michael Sattler, Hannes Mutschler, and Job Boekhoven

Subjects
Science
Abstract

Membraneless organelles are liquid-liquid phase-separated droplets whose behaviour can be regulated by chemical reactions, but this process is poorly understood. Here, the authors report model membraneless organelles based on coacervate droplets that show fuel-driven dynamic behaviour and concentrate functional RNA.

Published
2020
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26. Orphan GPR116 mediates the insulin sensitizing effects of the hepatokine FNDC4 in adipose tissue

Author

Georgiadi, Anastasia, Lopez-Salazar, Valeria, Merahbi, Rabih El-, Karikari, Rhoda Anane, Ma, Xiaochuan, Mourão, André, Klepac, Katarina, Bühler, Lea, Alfaro, Ana Jimena, Kaczmarek, Isabell, Linford, Adam, Bosma, Madeleen, Shilkova, Olga, Ritvos, Olli, Nakamura, Nobuhiro, Hirose, Shigehisa, Lassi, Maximilian, Teperino, Raffaele, Machado, Juliano, Scheideler, Marcel, Dietrich, Arne, Geerlof, Arie, Feuchtinger, Annette, Blutke, Andreas, Fischer, Katrin, Müller, Timo Dirk, Kessler, Katharina, Schöneberg, Torsten, Thor, Doreen, Hornemann, Silke, Kruse, Michael, Nawroth, Peter, Pivovarova-Ramich, Olga, Pfeiffer, Andreas Friedrich Hermann, Sattler, Michael, Blüher, Matthias, and Herzig, Stephan

Published
2021
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28. Bird population declines and species turnover are changing the acoustic properties of spring soundscapes

Author

Morrison, C. A., Auniņš, A., Benkő, Z., Brotons, L., Chodkiewicz, T., Chylarecki, P., Escandell, V., Eskildsen, D. P., Gamero, A., Herrando, S., Jiguet, F., Kålås, J. A., Kamp, J., Klvaňová, A., Kmecl, P., Lehikoinen, A., Lindström, Å., Moshøj, C., Noble, D. G., Øien, I. J., Paquet, J-Y., Reif, J., Sattler, T., Seaman, B. S., Teufelbauer, N., Trautmann, S., van Turnhout, C. A. M., Vořišek, P., and Butler, S. J.

Published
2021
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41. MICU1 controls cristae junction and spatially anchors mitochondrial Ca2+ uniporter complex

Author

Benjamin Gottschalk, Christiane Klec, Gerd Leitinger, Eva Bernhart, René Rost, Helmut Bischof, Corina T. Madreiter-Sokolowski, Snježana Radulović, Emrah Eroglu, Wolfgang Sattler, Markus Waldeck-Weiermair, Roland Malli, and Wolfgang F. Graier

Subjects
Science, lcsh:Q, lcsh:Science
Abstract

Proper mitochondrial structure is critical for normal function. Here, the authors show with SIM that the mitochondrial Ca2+ uniporter complex and localization of component MICU1 is critical to maintaining cristae junction stability and overall mitochondrial membrane structure.

Published
2019

42. The MTR4 helicase recruits nuclear adaptors of the human RNA exosome using distinct arch-interacting motifs

Author

Sebastian Falk, Torben Heick Jensen, Andreas Schlundt, Lukas M Langer, Mahesh Lingaraju, Elena Conti, Jérôme Basquin, Michael Sattler, and Dennis Johnsen

Subjects
0301 basic medicine, Exosome complex, Science, General Physics and Astronomy, RNA-binding protein, 02 engineering and technology, Biology, Crystallography, X-Ray, Exosomes, Ribosome, RNA decay, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, NMR spectroscopy, Protein Domains, ddc:570, Humans, Short linear motif, Amino Acid Sequence, lcsh:Science, RRNA processing, X-ray crystallography, Cell Nucleus, Multidisciplinary, Binding Sites, Sequence Homology, Amino Acid, Helicase, RNA, Nuclear Proteins, RNA-Binding Proteins, General Chemistry, 021001 nanoscience & nanotechnology, RNA Helicase A, Cell biology, ddc, 030104 developmental biology, Mutation, biology.protein, ATPases Associated with Diverse Cellular Activities, lcsh:Q, 0210 nano-technology, Carrier Proteins, RNA Helicases, HeLa Cells, Protein Binding
Abstract

The nuclear exosome and its essential co-factor, the RNA helicase MTR4, play crucial roles in several RNA degradation pathways. Besides unwinding RNA substrates for exosome-mediated degradation, MTR4 associates with RNA-binding proteins that function as adaptors in different RNA processing and decay pathways. Here, we identify and characterize the interactions of human MTR4 with a ribosome processing adaptor, NVL, and with ZCCHC8, an adaptor involved in the decay of small nuclear RNAs. We show that the unstructured regions of NVL and ZCCHC8 contain short linear motifs that bind the MTR4 arch domain in a mutually exclusive manner. These short sequences diverged from the arch-interacting motif (AIM) of yeast rRNA processing factors. Our results suggest that nuclear exosome adaptors have evolved canonical and non-canonical AIM sequences to target human MTR4 and demonstrate the versatility and specificity with which the MTR4 arch domain can recruit a repertoire of different RNA-binding proteins., The human RNA exosome contains a nuclear co-factor MTR4, which unwinds structural RNAs and recruits adaptors for different RNA processing and decay pathways. Here the authors uncover new variations of the arch-interacting motif (AIM) in NVL and ZCCHC8 and characterise their interaction with MTR4.

Published
2019

44. Negative regulation of EGFR signalling by the human folliculin tumour suppressor protein

Author

Wilhelm Haas, Julien Mermoud, Myriam Boukhali, Othon Iliopoulos, Dachuan Huang, Elisabeth Roider, Nicholas Olson, Mo Motamedi, Bin Tean Teh, Ortrud K. Steinlein, Laura A. Laviolette, Elke Sattler, and Isabel A. Calvo

Subjects
Male, 0301 basic medicine, Endosome, Science, General Physics and Astronomy, Mice, Transgenic, Endosomes, Biology, Article, General Biochemistry, Genetics and Molecular Biology, law.invention, Birt-Hogg-Dube Syndrome, 03 medical and health sciences, Germline mutation, Epidermal growth factor, law, Cell Line, Tumor, Proto-Oncogene Proteins, Schizosaccharomyces, Animals, Humans, Folliculin, EGFR inhibitors, Multidisciplinary, Tumor Suppressor Proteins, rab7 GTP-Binding Proteins, General Chemistry, Xenograft Model Antitumor Assays, Kidney Neoplasms, 3. Good health, ErbB Receptors, Mice, Inbred C57BL, 030104 developmental biology, RAB7A, rab GTP-Binding Proteins, Mutation, Cancer research, Suppressor, Female, Signal transduction, Signal Transduction
Abstract

Germline mutations in the Folliculin (FLCN) tumour suppressor gene result in fibrofolliculomas, lung cysts and renal cancers, but the precise mechanisms of tumour suppression by FLCN remain elusive. Here we identify Rab7A, a small GTPase important for endocytic trafficking, as a novel FLCN interacting protein and demonstrate that FLCN acts as a Rab7A GTPase-activating protein. FLCN−/− cells display slower trafficking of epidermal growth factor receptors (EGFR) from early to late endosomes and enhanced activation of EGFR signalling upon ligand stimulation. Reintroduction of wild-type FLCN, but not tumour-associated FLCN mutants, suppresses EGFR signalling in a Rab7A-dependent manner. EGFR signalling is elevated in FLCN−/− tumours and the EGFR inhibitor afatinib suppresses the growth of human FLCN−/− cells as tumour xenografts. The functional interaction between FLCN and Rab7A appears conserved across species. Our work highlights a mechanism explaining, at least in part, the tumour suppressor function of FLCN., Folliculin is a known tumour suppressor but the molecular mechanisms behind this function are unclear. Here the authors show that Folliculin regulates EGFR signalling by modulating its Rab7a-dependent trafficking.

Published
2017

45. The Hsp90 isoforms from S. cerevisiae differ in structure, function and client range

Author

Michael Sattler, Dominic Helm, Hannah Girstmair, Franziska Tippel, Katarzyna M. Tych, Frank Stein, Philipp W. N. Schmid, Johannes Buchner, Per Haberkant, Abraham Lopez, and Matthias Rief

Subjects
0301 basic medicine, Models, Molecular, Protein Folding, Cell biology, Saccharomyces cerevisiae Proteins, Protein Conformation, Science, Regulator, Biophysics, General Physics and Astronomy, 02 engineering and technology, Saccharomyces cerevisiae, Ligands, Biochemistry, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Protein structure, Stress, Physiological, Chaperones, Protein Isoforms, Amino Acid Sequence, HSP90 Heat-Shock Proteins, lcsh:Science, Adenosine Triphosphatases, Multidisciplinary, biology, Chemistry, Protein Stability, General Chemistry, 021001 nanoscience & nanotechnology, Hsp90, ddc, 030104 developmental biology, Proteostasis, Structural biology, Chaperone (protein), biology.protein, lcsh:Q, Protein folding, 0210 nano-technology, Sequence Alignment, Function (biology), Heat-Shock Response, Molecular Chaperones, Protein Binding
Abstract

The molecular chaperone Hsp90 is an important regulator of proteostasis. It has remained unclear why S. cerevisiae possesses two Hsp90 isoforms, the constitutively expressed Hsc82 and the stress-inducible Hsp82. Here, we report distinct differences despite a sequence identity of 97%. Consistent with its function under stress conditions, Hsp82 is more stable and refolds more efficiently than Hsc82. The two isoforms also differ in their ATPases and conformational cycles. Hsc82 is more processive and populates closed states to a greater extent. Variations in the N-terminal ATP-binding domain modulate its dynamics and conformational cycle. Despite these differences, the client interactomes are largely identical, but isoform-specific interactors exist both under physiological and heat shock conditions. Taken together, changes mainly in the N-domain create a stress-specific, more resilient protein with a shifted activity profile. Thus, the precise tuning of the Hsp90 isoforms preserves the basic mechanism but adapts it to specific needs., S. cerevisiae encodes two Hsp90 isoforms, the constitutively expressed Hsc82 and stress-inducible Hsp82 that are 97% identical. Here, the authors combine a range of biophysical methods and show that they differ in their enzymatic properties, resilience to stress and client range, which suggests that they evolved to provide fine-tuned chaperone assistance under physiological and stress conditions.

Published
2019

46. Molecular basis for CPAP-tubulin interaction in controlling centriolar and ciliary length

Author

Li Ming Gooi, Komal Soni, Haiteng Deng, Xiangdong Zheng, Aruljothi Mariappan, Guangshuo Ou, Andrei Pozniakovsky, Michael Sattler, Jay Gopalakrishnan, Anthony A. Hyman, Arpit Wason, Callaini Giuliano, Haitao Li, Maria Giovanna Riparbelli, Ina Poser, Marco Gottardo, Per O. Widlund, Wenjing Li, Shan Feng, Anand Ramani, and Shuangping Zheng

Subjects
Models, Molecular, Protein Conformation, alpha-Helical, 0301 basic medicine, Genetics and Molecular Biology (all), Centriole, Swine, Gene Expression, General Physics and Astronomy, Plasma protein binding, Crystallography, X-Ray, Microtubules, Biochemistry, Tubulin, Protein Isoforms, Cloning, Molecular, Centrioles, Multidisciplinary, Cilium, Chemistry (all), Recombinant Proteins, Cell biology, Microtubule-Associated Proteins, Protein Binding, Microtubule-associated protein, Science, macromolecular substances, Biology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Physics and Astronomy (all), Microtubule, Escherichia coli, Animals, Humans, Protein Interaction Domains and Motifs, Amino Acid Sequence, Cilia, Binding site, Binding Sites, Sequence Homology, Amino Acid, General Chemistry, 030104 developmental biology, Cytoplasm, Biochemistry, Genetics and Molecular Biology (all), Mutation, biology.protein, Cattle, Protein Conformation, beta-Strand, Sequence Alignment, HeLa Cells
Abstract

Centrioles and cilia are microtubule-based structures, whose precise formation requires controlled cytoplasmic tubulin incorporation. How cytoplasmic tubulin is recognized for centriolar/ciliary-microtubule construction remains poorly understood. Centrosomal-P4.1-associated-protein (CPAP) binds tubulin via its PN2-3 domain. Here, we show that a C-terminal loop-helix in PN2-3 targets β-tubulin at the microtubule outer surface, while an N-terminal helical motif caps microtubule's α-β surface of β-tubulin. Through this, PN2-3 forms a high-affinity complex with GTP-tubulin, crucial for defining numbers and lengths of centriolar/ciliary-microtubules. Surprisingly, two distinct mutations in PN2-3 exhibit opposite effects on centriolar/ciliary-microtubule lengths. CPAPF375A, with strongly reduced tubulin interaction, causes shorter centrioles and cilia exhibiting doublet- instead of triplet-microtubules. CPAPEE343RR that unmasks the β-tubulin polymerization surface displays slightly reduced tubulin-binding affinity inducing over-elongation of newly forming centriolar/ciliary-microtubules by enhanced dynamic release of its bound tubulin. Thus CPAP regulates delivery of its bound-tubulin to define the size of microtubule-based cellular structures using a ‘clutch-like' mechanism., Centrioles and cilia are microtubule-based structures of defined architecture, but what regulates this architecture is not clear. Here the authors discover that centrosomal-P4.1-associated-protein (CPAP) binds the α/β-tubulin dimer and licenses it for tubulin delivery contributing to centriolar/ciliary length and architecture control.

Published
2016

47. MICU1 controls cristae junction and spatially anchors mitochondrial Ca

Author

Benjamin, Gottschalk, Christiane, Klec, Gerd, Leitinger, Eva, Bernhart, René, Rost, Helmut, Bischof, Corina T, Madreiter-Sokolowski, Snježana, Radulović, Emrah, Eroglu, Wolfgang, Sattler, Markus, Waldeck-Weiermair, Roland, Malli, and Wolfgang F, Graier

Subjects
Membrane Potential, Mitochondrial, Calcium-Binding Proteins, Calcium signalling, Mitochondrial Membrane Transport Proteins, Article, Mitochondria, HEK293 Cells, Cell Line, Tumor, Mitochondrial Membranes, MCF-7 Cells, Humans, Calcium, Calcium Channels, Calcium Signaling, Super-resolution microscopy, Cation Transport Proteins, HeLa Cells
Abstract

Recently identified core proteins (MICU1, MCU, EMRE) forming the mitochondrial Ca2+ uniporter complex propelled investigations into its physiological workings. Here, we apply structured illumination microscopy to visualize and localize these proteins in living cells. Our data show that MICU1 localizes at the inner boundary membrane (IBM) due to electrostatic interaction of its polybasic domain. Moreover, this exclusive localization of MICU1 is important for the stability of cristae junctions (CJ), cytochrome c release and mitochondrial membrane potential. In contrast to MICU1, MCU and EMRE are homogeneously distributed at the inner mitochondrial membrane under resting conditions. However, upon Ca2+ elevation MCU and EMRE dynamically accumulate at the IBM in a MICU1-dependent manner. Eventually, our findings unveil an essential function of MICU1 in CJ stabilization and provide mechanistic insights of how sophistically MICU1 controls the MCU-Complex while maintaining the structural mitochondrial membrane framework., Proper mitochondrial structure is critical for normal function. Here, the authors show with SIM that the mitochondrial Ca2+ uniporter complex and localization of component MICU1 is critical to maintaining cristae junction stability and overall mitochondrial membrane structure.

Published
2018

48. Roquin targets mRNAs in a 3'-UTR-specific manner by different modes of regulation

Author

Gesine Behrens, Andreas Schlundt, Joao C. Guimaraes, Jacek Jemielity, Mihaela Zavolan, Vigo Heissmeyer, Michael Sattler, Kristin Reiche, Helmut Holtmann, Sven Brenner, Jörg Hackermüller, Cristina López-Rodríguez, Anne Hoffmann, Claudia Lohs, Katharina Essig, Nina Kronbeck, Joanna Kowalska, and Publica

Subjects
0301 basic medicine, Translation, Science, RNA Stability, Ubiquitin-Protein Ligases, Response element, Amino Acid Motifs, General Physics and Astronomy, Autoimmunity, Plasma protein binding, Biology, Response Elements, RNA decay, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Mice, 0302 clinical medicine, Gene expression, Animals, Humans, RNA folding, RNA, Messenger, lcsh:Science, Psychological repression, 3' Untranslated Regions, Regulation of gene expression, Messenger RNA, Multidisciplinary, Binding Sites, Base Sequence, Three prime untranslated region, General Chemistry, NFKBID, Cell biology, 030104 developmental biology, Cross-Linking Reagents, Gene Expression Regulation, Protein Biosynthesis, Nucleic Acid Conformation, lcsh:Q, Ribonucleosides, Transcriptome, 030217 neurology & neurosurgery, HeLa Cells, Protein Binding
Abstract

The RNA-binding proteins Roquin-1 and Roquin-2 redundantly control gene expression and cell-fate decisions. Here, we show that Roquin not only interacts with stem–loop structures, but also with a linear sequence element present in about half of its targets. Comprehensive analysis of a minimal response element of the Nfkbid 3′-UTR shows that six stem–loop structures cooperate to exert robust and profound post-transcriptional regulation. Only binding of multiple Roquin proteins to several stem–loops exerts full repression, which redundantly involved deadenylation and decapping, but also translational inhibition. Globally, most Roquin targets are regulated by mRNA decay, whereas a small subset, including the Nfat5 mRNA, with more binding sites in their 3′-UTRs, are also subject to translational inhibition. These findings provide insights into how the robustness and magnitude of Roquin-mediated regulation is encoded in complex cis-elements.

Published
2018

49. Allosteric modulation of peroxisomal membrane protein recognition by farnesylation of the peroxisomal import receptor PEX19

Author

Tobias Madl, Wolfgang Schliebs, Juliane Radke, Ulrike Schütz, Michael Sattler, Leonidas Emmanouilidis, Konstantinos Tripsianes, Matthias Wilmanns, Ralf Erdmann, and Robert Rucktäschel

Subjects
0301 basic medicine, Protein Conformation, alpha-Helical, General Physics and Astronomy, Gene Expression, Plasma protein binding, environment and public health, Protein structure, Zellweger Syndrome, Multidisciplinary, biology, Chemistry, Peroxisome, Recombinant Proteins, Cell biology, Molecular Docking Simulation, lipids (amino acids, peptides, and proteins), Hydrophobic and Hydrophilic Interactions, Protein Binding, Saccharomyces cerevisiae Proteins, Science, Allosteric regulation, Saccharomyces cerevisiae, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Prenylation, Allosteric Regulation, Peroxisomes, Humans, Protein Interaction Domains and Motifs, Amino Acid Sequence, Peroxisomal targeting signal, Alkyl and Aryl Transferases, Binding Sites, 030102 biochemistry & molecular biology, Sequence Homology, Amino Acid, organic chemicals, Membrane Proteins, General Chemistry, Fibroblasts, 030104 developmental biology, Membrane protein, Chaperone (protein), Mutation, biology.protein, Protein Conformation, beta-Strand, Protein Processing, Post-Translational, Sequence Alignment
Abstract

The transport of peroxisomal membrane proteins (PMPs) requires the soluble PEX19 protein as chaperone and import receptor. Recognition of cargo PMPs by the C-terminal domain (CTD) of PEX19 is required for peroxisome biogenesis in vivo. Farnesylation at a C-terminal CaaX motif in PEX19 enhances the PMP interaction, but the underlying molecular mechanisms are unknown. Here, we report the NMR-derived structure of the farnesylated human PEX19 CTD, which reveals that the farnesyl moiety is buried in an internal hydrophobic cavity. This induces substantial conformational changes that allosterically reshape the PEX19 surface to form two hydrophobic pockets for the recognition of conserved aromatic/aliphatic side chains in PMPs. Mutations of PEX19 residues that either mediate farnesyl contacts or are directly involved in PMP recognition abolish cargo binding and cannot complement a ΔPEX19 phenotype in human Zellweger patient fibroblasts. Our results demonstrate an allosteric mechanism for the modulation of protein function by farnesylation., PEX19 is a chaperone and import receptor for peroxisomal membrane proteins (PMPs). Here the authors present the structure of the farnesylated C-terminal domain of PEX19, and its interaction with PMPs reveals how the farnesyl moiety allosterically reshapes the PMP binding surface and modulates PEX19 function.

Published
2017

50. Combinatorial recognition of clustered RNA elements by the multidomain RNA-binding protein IMP3

Author

Tim, Schneider, Lee-Hsueh, Hung, Masood, Aziz, Anna, Wilmen, Stephanie, Thaum, Jacqueline, Wagner, Robert, Janowski, Simon, Müller, Silke, Schreiner, Peter, Friedhoff, Stefan, Hüttelmaier, Dierk, Niessing, Michael, Sattler, Andreas, Schlundt, Albrecht, Bindereif, and Institute of Biochemistry

Subjects
Models, Molecular, RNA metabolism, Chemistry & allied sciences, Science, SELEX Aptamer Technique, High-Throughput Nucleotide Sequencing, RNA-Binding Proteins, Sequence Analysis, DNA, macromolecular substances, environment and public health, Recombinant Proteins, Article, carbohydrates (lipids), enzymes and coenzymes (carbohydrates), Gene Expression Regulation, ddc:540, RNA-Binding Motifs, health occupations, lcsh:Q, RNA, Messenger, Structural biology, lcsh:Science, Protein Binding
Abstract

How multidomain RNA-binding proteins recognize their specific target sequences, based on a combinatorial code, represents a fundamental unsolved question and has not been studied systematically so far. Here we focus on a prototypical multidomain RNA-binding protein, IMP3 (also called IGF2BP3), which contains six RNA-binding domains (RBDs): four KH and two RRM domains. We establish an integrative systematic strategy, combining single-domain-resolved SELEX-seq, motif-spacing analyses, in vivo iCLIP, functional validation assays, and structural biology. This approach identifies the RNA-binding specificity and RNP topology of IMP3, involving all six RBDs and a cluster of up to five distinct and appropriately spaced CA-rich and GGC-core RNA elements, covering a >100 nucleotide-long target RNA region. Our generally applicable approach explains both specificity and flexibility of IMP3-RNA recognition, allows the prediction of IMP3 targets, and provides a paradigm for the function of multivalent interactions with multidomain RNA-binding proteins in gene regulation., Multidomain RNA-binding proteins recognize specific target sequences through mechanisms that are not well understood. Here the authors present an integrated approach to define the RNA-binding specificity and RNP topology and apply it to the analysis of the prototypical multidomain RNA-binding protein IMP3.

Published
2019

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