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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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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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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. |
format | Online Article Text |
id | pubmed-9479151 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
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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