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540 results on '"Lanzer, Michael"'

20. The role of Plasmodium V-ATPase in vacuolar physiology and antimalarial drug uptake

Author

Alder, Arne, Sanchez, Cecilia P, Russell, Matthew RG, Collinson, Lucy M, Lanzer, Michael, Blackman, Michael J, Gilberger, Tim-Wolf, and Matz, Joachim M

Subjects
Model organisms, FOS: Clinical medicine, Immunology, Infectious Disease, Cell Biology, Biochemistry & Proteomics, Imaging, Structural Biology & Biophysics
Abstract

To ensure their survival in the human bloodstream, malaria parasites degrade up to 80% of the host erythrocyte hemoglobin in an acidified digestive vacuole. Here, we combine conditional reverse genetics and quantitative imaging approaches to demonstrate that the human malaria pathogen Plasmodium falciparum employs a heteromultimeric V-ATPase complex to acidify the digestive vacuole matrix, which is essential for intravacuolar hemoglobin release, heme detoxification, and parasite survival. We reveal an additional function of the membrane-embedded V-ATPase subunits in regulating morphogenesis of the digestive vacuole independent of proton translocation. We further show that intravacuolar accumulation of antimalarial chemotherapeutics is surprisingly resilient to severe deacidification of the vacuole and that modulation of V-ATPase activity does not affect parasite sensitivity toward these drugs.

Published
2023
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22. The Knock-Down of the Chloroquine Resistance Transporter PfCRT Is Linked to Oligopeptide Handling in Plasmodium falciparum

Author

Sanchez, Cecilia P., Manson, Erin D. T., Moliner Cubel, Sonia, Mandel, Luis, Weidt, Stefan K., Barrett, Michael P., and Lanzer, Michael

Subjects
Microbiology (medical), General Immunology and Microbiology, Ecology, Physiology, Plasmodium falciparum, Protozoan Proteins, Membrane Transport Proteins, Chloroquine, Cell Biology, Malaria, Antimalarials, Infectious Diseases, Genetics, Humans, Malaria, Falciparum, Oligopeptides
Abstract

The chloroquine resistance transporter, PfCRT, is an essential factor during intraerythrocytic development of the human malaria parasite Plasmodium falciparum. PfCRT resides at the digestive vacuole of the parasite, where hemoglobin taken up by the parasite from its host cell is degraded. PfCRT can acquire several mutations that render PfCRT a drug transporting system expelling compounds targeting hemoglobin degradation from the digestive vacuole. The non-drug related function of PfCRT is less clear, although a recent study has suggested a role in oligopeptide transport based on studies conducted in a heterologous expression system. The uncertainty about the natural function of PfCRT is partly due to a lack of a null mutant and a dearth of functional assays in the parasite. Here, we report on the generation of a conditional PfCRT knock-down mutant in P. falciparum. The mutant accumulated oligopeptides 2 to at least 8 residues in length under knock-down conditions, as shown by comparative global metabolomics. The accumulated oligopeptides were structurally diverse, had an isoelectric point between 4.0 and 5.4 and were electrically neutral or carried a single charge at the digestive vacuolar pH of 5.2. Fluorescently labeled dipeptides and live cell imaging identified the digestive vacuole as the compartment where oligopeptides accumulated. Our findings suggest a function of PfCRT in oligopeptide transport across the digestive vacuolar membrane in P. falciparum and associated with it a role in nutrient acquisition and the maintenance of the colloid osmotic balance.

Published
2022

25. Verstopfte Nase

Author

Lanzer, Michael, Geiss, Heinrich K., editor, Jacobs, Enno, editor, and Mack, Dietrich, editor

Published
2008
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26. KAHRP dynamically relocalizes to remodeled actin junctions and associates with knob spirals in Plasmodium falciparum-infected erythrocytes

Author

Sanchez, Cecilia P., Patra, Pintu, Scott Chang, Shih-Ying, Karathanasis, Christos, Hanebutte, Lukas, Kilian, Nicole, Cyrklaff, Marek, Heilemann, Mike, Schwarz, Ulrich S., Kudryashev, Mikhail, and Lanzer, Michael

Subjects
Cancer Research, ddc:570, ddc:540, parasitic diseases, ddc:610
Abstract

The knob-associated histidine-rich protein (KAHRP) plays a pivotal role in the pathophysiology of Plasmodium falciparum malaria by forming membrane protrusions in infected erythrocytes, which anchor parasite-encoded adhesins to the membrane skeleton. The resulting sequestration of parasitized erythrocytes in the microvasculature leads to severe disease. Despite KAHRP being an important virulence factor, its physical location within the membrane skeleton is still debated, as is its function in knob formation. Here, we show by super-resolution microscopy that KAHRP initially associates with various skeletal components, including ankyrin bridges, but eventually colocalizes with remnant actin junctions. We further present a 35 Å map of the spiral scaffold underlying knobs and show that a KAHRP-targeting nanoprobe binds close to the spiral scaffold. Single-molecule localization microscopy detected ~60 KAHRP molecules/knob. We propose a dynamic model of KAHRP organization and a function of KAHRP in attaching other factors to the spiral scaffold.

Published
2022

29. Transcellular blood–brain barrier disruption in malaria-induced reversible brain edema

Author

Jin, Jessica, primary, Ba, Mame Aida, additional, Wai, Chi Ho, additional, Mohanty, Sanjib, additional, Sahu, Praveen K, additional, Pattnaik, Rajyabardhan, additional, Pirpamer, Lukas, additional, Fischer, Manuel, additional, Heiland, Sabine, additional, Lanzer, Michael, additional, Frischknecht, Friedrich, additional, Mueller, Ann-Kristin, additional, Pfeil, Johannes, additional, Majhi, Megharay, additional, Cyrklaff, Marek, additional, Wassmer, Samuel C, additional, Bendszus, Martin, additional, and Hoffmann, Angelika, additional

Published
2022
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35. Reversible brain edema in experimental cerebral malaria is associated with transcellular blood-brain barrier disruption and delayed microhemorrhages

Author

Jin, Jessica, primary, Ba, Mame Aida, additional, Wai, Chi Ho, additional, Mohanty, Sanjib, additional, Sahu, Praveen K., additional, Pattnaik, Rajyabardham, additional, Pirpamer, Lukas, additional, Fischer, Manuel, additional, Heiland, Sabine, additional, Lanzer, Michael, additional, Frischknecht, Friedrich, additional, Mueller, Ann-Kristin, additional, Pfeil, Johannes, additional, Majhi, Megharay, additional, Cyrklaff, Marek, additional, Wassmer, Samuel C., additional, Bendszus, Martin, additional, and Hoffmann, Angelika, additional

Published
2021
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39. KAHRP dynamically relocalizes to remodeled actin junctions and associates with knob spirals in Plasmodium falciparum ‐infected erythrocytes

Author

Sanchez, Cecilia P., primary, Patra, Pintu, additional, Chang, Shih‐Ying Scott, additional, Karathanasis, Christos, additional, Hanebutte, Lukas, additional, Kilian, Nicole, additional, Cyrklaff, Marek, additional, Heilemann, Mike, additional, Schwarz, Ulrich S., additional, Kudryashev, Mikhail, additional, and Lanzer, Michael, additional

Published
2021
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42. Balancing drug resistance and growth rates via compensatory mutations in the Plasmodium falciparum chloroquine resistance transporter

Author

Petersen, Ines, Gabryszewski, Stanislaw J., Johnston, Geoffrey L., Dhingra, Satish K., Ecker, Andrea, Lewis, Rebecca E., de Almeida, Mariana Justino, Straimer, Judith, Henrich, Philipp P., Palatulan, Eugene, Johnson, David J., Coburn-Flynn, Olivia, Sanchez, Cecilia, Lehane, Adele M., Lanzer, Michael, and Fidock, David A.

Published
2015
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47. Author Reply to Peer Reviews of KAHRP dynamically relocalizes to remodeled actin junctions and associates with knob spirals in P. falciparum-infected erythrocytes

Author

Lanzer, Michael, primary, Kudryashev, Mikhail, additional, Schwarz, Ulrich S., additional, Heilemann, Mike, additional, Cyrklaff, Marek, additional, Kilian, Nicole, additional, Hanebutte, Lukas, additional, Karathanasis, Christos, additional, Chang, Shih-Ying, additional, Patra, Pintu, additional, and Sanchez, Cecilia P., additional

Published
2021
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49. Structure of the merozoite surface protein 1 from Plasmodium falciparum

Author

Dijkman, Patricia M., Marzluf, Tanja, Zhang, Yingying, Chang, Shih-Ying Scott, Helm, Dominic, Lanzer, Michael, Bujard, Hermann, Kudryashev, Mikhail, Dijkman, Patricia M., Marzluf, Tanja, Zhang, Yingying, Chang, Shih-Ying Scott, Helm, Dominic, Lanzer, Michael, Bujard, Hermann, and Kudryashev, Mikhail

Abstract

The merozoite surface protein 1 (MSP-1) is the most abundant protein on the surface of the erythrocyte-invading Plasmodium merozoite, the causative agent of malaria. MSP-1 is essential for merozoite formation, entry into and escape from erythrocytes, and is a promising vaccine candidate. Here, we present monomeric and dimeric structures of full-length MSP-1. MSP-1 adopts an unusual fold with a large central cavity. Its fold includes several coiled-coils and shows structural homology to proteins associated with membrane and cytoskeleton interactions. MSP-1 formed dimers through these domains in a concentration-dependent manner. Dimerization is affected by the presence of the erythrocyte cytoskeleton protein spectrin, which may compete for the dimerization interface. Our work provides structural insights into the possible mode of interaction of MSP-1 with erythrocytes and establishes a framework for future investigations into the role of MSP-1 in Plasmodium infection and immunity.

Published
2021

50. KAHRP dynamically relocalizes to remodeled actin junctions and associates with knob spirals in Plasmodium falciparum-infected erythrocytes

Author

Sanchez, Cecilia P., Patra, Pintu, Scott Chang, Shih-Ying, Karathanasis, Christos, Hanebutte, Lukas, Kilian, Nicole, Cyrklaff, Marek, Heilemann, Mike, Schwarz, Ulrich S., Kudryashev, Mikhail, Lanzer, Michael, Sanchez, Cecilia P., Patra, Pintu, Scott Chang, Shih-Ying, Karathanasis, Christos, Hanebutte, Lukas, Kilian, Nicole, Cyrklaff, Marek, Heilemann, Mike, Schwarz, Ulrich S., Kudryashev, Mikhail, and Lanzer, Michael

Abstract

The knob-associated histidine-rich protein (KAHRP) plays a pivotal role in the pathophysiology of Plasmodium falciparum malaria by forming membrane protrusions in infected erythrocytes, which anchor parasite-encoded adhesins to the membrane skeleton. The resulting sequestration of parasitized erythrocytes in the microvasculature leads to severe disease. Despite KAHRP being an important virulence factor, its physical location within the membrane skeleton is still debated, as is its function in knob formation. Here, we show by super-resolution microscopy that KAHRP initially associates with various skeletal components, including ankyrin bridges, but eventually colocalizes with remnant actin junctions. We further present a 35 Å map of the spiral scaffold underlying knobs and show that a KAHRP-targeting nanoprobe binds close to the spiral scaffold. Single-molecule localization microscopy detected ~60 KAHRP molecules/knob. We propose a dynamic model of KAHRP organization and a function of KAHRP in attaching other factors to the spiral scaffold.

Published
2021

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