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Phosphatidylserine orchestrates Myomerger membrane insertions to drive myoblast fusion

Muscle cell fusion is a multistep process where the final step of the reaction drives progression beyond early hemifusion events to complete fusion. This step requires activity of the muscle-specific fusogen Myomerger, a single-pass transmembrane protein containing 84 amino acids with an ectodomain...

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Autores principales: Gamage, Dilani G., Melikov, Kamran, Munoz-Tello, Paola, Wherley, Tanner J., Focke, Leah C., Leikina, Evgenia, Huffman, Elliana, Diao, Jiajie, Kojetin, Douglas J., Prasad, Vikram, Chernomordik, Leonid V., Millay, Douglas P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9499509/
https://www.ncbi.nlm.nih.gov/pubmed/36095199
http://dx.doi.org/10.1073/pnas.2202490119
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author Gamage, Dilani G.
Melikov, Kamran
Munoz-Tello, Paola
Wherley, Tanner J.
Focke, Leah C.
Leikina, Evgenia
Huffman, Elliana
Diao, Jiajie
Kojetin, Douglas J.
Prasad, Vikram
Chernomordik, Leonid V.
Millay, Douglas P.
author_facet Gamage, Dilani G.
Melikov, Kamran
Munoz-Tello, Paola
Wherley, Tanner J.
Focke, Leah C.
Leikina, Evgenia
Huffman, Elliana
Diao, Jiajie
Kojetin, Douglas J.
Prasad, Vikram
Chernomordik, Leonid V.
Millay, Douglas P.
author_sort Gamage, Dilani G.
collection PubMed
description Muscle cell fusion is a multistep process where the final step of the reaction drives progression beyond early hemifusion events to complete fusion. This step requires activity of the muscle-specific fusogen Myomerger, a single-pass transmembrane protein containing 84 amino acids with an ectodomain that includes two α-helices. Previous studies have demonstrated that Myomerger acts by destabilizing membranes through generation of elastic stresses in the outer leaflet of the plasma membrane. An obvious question is how such destabilizing activity might be regulated to avoid membrane and cellular damage, and how the two juxtaposed helices cooperate in fusion. Using cellular fusion assays and in vitro liposome assays, we report that the two helices possess unique characteristics, both of which are needed for full activity of the protein. We demonstrate that externalized phosphatidylserine (PS), a lipid previously implicated in myoblast fusion, has a determinant role in the regulation of Myomerger activity. The membrane-proximal, amphipathic Helix-1 is normally disordered and its α-helical structure is induced by PS, making membrane interactions more efficacious. The distal, more hydrophobic Helix-2 is intrinsically ordered, possesses an ability to insert into membranes, and augments the membrane-stressing effects of Helix-1. These data reveal that Myomerger fusogenic activity is an exquisitely orchestrated event involving its two ectodomain helices, which are controlled by membrane lipid composition, providing an explanation as to how its membrane-stressing activity is spatially and temporally regulated during the final step of myoblast fusion.
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spelling pubmed-94995092023-03-12 Phosphatidylserine orchestrates Myomerger membrane insertions to drive myoblast fusion Gamage, Dilani G. Melikov, Kamran Munoz-Tello, Paola Wherley, Tanner J. Focke, Leah C. Leikina, Evgenia Huffman, Elliana Diao, Jiajie Kojetin, Douglas J. Prasad, Vikram Chernomordik, Leonid V. Millay, Douglas P. Proc Natl Acad Sci U S A Biological Sciences Muscle cell fusion is a multistep process where the final step of the reaction drives progression beyond early hemifusion events to complete fusion. This step requires activity of the muscle-specific fusogen Myomerger, a single-pass transmembrane protein containing 84 amino acids with an ectodomain that includes two α-helices. Previous studies have demonstrated that Myomerger acts by destabilizing membranes through generation of elastic stresses in the outer leaflet of the plasma membrane. An obvious question is how such destabilizing activity might be regulated to avoid membrane and cellular damage, and how the two juxtaposed helices cooperate in fusion. Using cellular fusion assays and in vitro liposome assays, we report that the two helices possess unique characteristics, both of which are needed for full activity of the protein. We demonstrate that externalized phosphatidylserine (PS), a lipid previously implicated in myoblast fusion, has a determinant role in the regulation of Myomerger activity. The membrane-proximal, amphipathic Helix-1 is normally disordered and its α-helical structure is induced by PS, making membrane interactions more efficacious. The distal, more hydrophobic Helix-2 is intrinsically ordered, possesses an ability to insert into membranes, and augments the membrane-stressing effects of Helix-1. These data reveal that Myomerger fusogenic activity is an exquisitely orchestrated event involving its two ectodomain helices, which are controlled by membrane lipid composition, providing an explanation as to how its membrane-stressing activity is spatially and temporally regulated during the final step of myoblast fusion. National Academy of Sciences 2022-09-12 2022-09-20 /pmc/articles/PMC9499509/ /pubmed/36095199 http://dx.doi.org/10.1073/pnas.2202490119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Gamage, Dilani G.
Melikov, Kamran
Munoz-Tello, Paola
Wherley, Tanner J.
Focke, Leah C.
Leikina, Evgenia
Huffman, Elliana
Diao, Jiajie
Kojetin, Douglas J.
Prasad, Vikram
Chernomordik, Leonid V.
Millay, Douglas P.
Phosphatidylserine orchestrates Myomerger membrane insertions to drive myoblast fusion
title Phosphatidylserine orchestrates Myomerger membrane insertions to drive myoblast fusion
title_full Phosphatidylserine orchestrates Myomerger membrane insertions to drive myoblast fusion
title_fullStr Phosphatidylserine orchestrates Myomerger membrane insertions to drive myoblast fusion
title_full_unstemmed Phosphatidylserine orchestrates Myomerger membrane insertions to drive myoblast fusion
title_short Phosphatidylserine orchestrates Myomerger membrane insertions to drive myoblast fusion
title_sort phosphatidylserine orchestrates myomerger membrane insertions to drive myoblast fusion
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9499509/
https://www.ncbi.nlm.nih.gov/pubmed/36095199
http://dx.doi.org/10.1073/pnas.2202490119
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