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Not sorcery after all: Roles of multiple charged residues in membrane insertion of gasdermin-A3

Gasdermins execute programmatory cell death, known as pyroptosis, by forming medium-sized membrane pores. Recently, the molecular structure of those pores as well as the diversity in their shape and size have been revealed by cryoTEM and atomic force microscopy, respectively. Even though a growth of...

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Autores principales: Korn, Viktoria, Pluhackova, Kristyna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9479151/
https://www.ncbi.nlm.nih.gov/pubmed/36120563
http://dx.doi.org/10.3389/fcell.2022.958957
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author Korn, Viktoria
Pluhackova, Kristyna
author_facet Korn, Viktoria
Pluhackova, Kristyna
author_sort Korn, Viktoria
collection PubMed
description Gasdermins execute programmatory cell death, known as pyroptosis, by forming medium-sized membrane pores. Recently, the molecular structure of those pores as well as the diversity in their shape and size have been revealed by cryoTEM and atomic force microscopy, respectively. Even though a growth of smaller to larger oligomers and reshaping from slits to rings could be documented, the initiation of the gasdermin pore formation remains a mystery. In one hypothesis, gasdermin monomers insert into membranes before associating into oligomeric pores. In the other hypothesis, gasdermin oligomers preassemble on the membrane surface prior to membrane insertion. Here, by studying the behavior of monomeric membrane-inserted gasdermin-A3 (GSDMA3), we unveil that a monomeric gasdermin prefers the membrane-adsorbed over the membrane-inserted state. Our results thus support the hypothesis of oligomers preassembling on the membrane surface before membrane penetration. At the same time, our simulations of small membrane-inserted arcs of GSDMA3 suggest that the inserting oligomer can be small and does not have to comprise a full ring of approximately 26–30 subunits. Moreover, our simulations have revealed an astonishingly large impact of salt-bridge formation and protein surroundings on the transmembrane passage of charged residues, reducing the energetic cost by up to 53% as compared to their free forms. The here observed free energy barrier of mere 5.6 kcal/mol for the membrane insertion of monomeric GSDMA3 explains the surprising ability of gasdermins to spontaneously self-insert into cellular membranes.
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spelling pubmed-94791512022-09-17 Not sorcery after all: Roles of multiple charged residues in membrane insertion of gasdermin-A3 Korn, Viktoria Pluhackova, Kristyna Front Cell Dev Biol Cell and Developmental Biology Gasdermins execute programmatory cell death, known as pyroptosis, by forming medium-sized membrane pores. Recently, the molecular structure of those pores as well as the diversity in their shape and size have been revealed by cryoTEM and atomic force microscopy, respectively. Even though a growth of smaller to larger oligomers and reshaping from slits to rings could be documented, the initiation of the gasdermin pore formation remains a mystery. In one hypothesis, gasdermin monomers insert into membranes before associating into oligomeric pores. In the other hypothesis, gasdermin oligomers preassemble on the membrane surface prior to membrane insertion. Here, by studying the behavior of monomeric membrane-inserted gasdermin-A3 (GSDMA3), we unveil that a monomeric gasdermin prefers the membrane-adsorbed over the membrane-inserted state. Our results thus support the hypothesis of oligomers preassembling on the membrane surface before membrane penetration. At the same time, our simulations of small membrane-inserted arcs of GSDMA3 suggest that the inserting oligomer can be small and does not have to comprise a full ring of approximately 26–30 subunits. Moreover, our simulations have revealed an astonishingly large impact of salt-bridge formation and protein surroundings on the transmembrane passage of charged residues, reducing the energetic cost by up to 53% as compared to their free forms. The here observed free energy barrier of mere 5.6 kcal/mol for the membrane insertion of monomeric GSDMA3 explains the surprising ability of gasdermins to spontaneously self-insert into cellular membranes. Frontiers Media S.A. 2022-09-02 /pmc/articles/PMC9479151/ /pubmed/36120563 http://dx.doi.org/10.3389/fcell.2022.958957 Text en Copyright © 2022 Korn and Pluhackova. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Korn, Viktoria
Pluhackova, Kristyna
Not sorcery after all: Roles of multiple charged residues in membrane insertion of gasdermin-A3
title Not sorcery after all: Roles of multiple charged residues in membrane insertion of gasdermin-A3
title_full Not sorcery after all: Roles of multiple charged residues in membrane insertion of gasdermin-A3
title_fullStr Not sorcery after all: Roles of multiple charged residues in membrane insertion of gasdermin-A3
title_full_unstemmed Not sorcery after all: Roles of multiple charged residues in membrane insertion of gasdermin-A3
title_short Not sorcery after all: Roles of multiple charged residues in membrane insertion of gasdermin-A3
title_sort not sorcery after all: roles of multiple charged residues in membrane insertion of gasdermin-a3
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9479151/
https://www.ncbi.nlm.nih.gov/pubmed/36120563
http://dx.doi.org/10.3389/fcell.2022.958957
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