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FerA is a Membrane-Associating Four-Helix Bundle Domain in the Ferlin Family of Membrane-Fusion Proteins

Ferlin proteins participate in such diverse biological events as vesicle fusion in C. elegans, fusion of myoblast membranes to form myotubes, Ca(2+)-sensing during exocytosis in the hair cells of the inner ear, and Ca(2+)-dependent membrane repair in skeletal muscle cells. Ferlins are Ca(2+)-depende...

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Autores principales: Harsini, Faraz M., Chebrolu, Sukanya, Fuson, Kerry L., White, Mark A., Rice, Anne M., Sutton, R. Bryan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053371/
https://www.ncbi.nlm.nih.gov/pubmed/30026467
http://dx.doi.org/10.1038/s41598-018-29184-1
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author Harsini, Faraz M.
Chebrolu, Sukanya
Fuson, Kerry L.
White, Mark A.
Rice, Anne M.
Sutton, R. Bryan
author_facet Harsini, Faraz M.
Chebrolu, Sukanya
Fuson, Kerry L.
White, Mark A.
Rice, Anne M.
Sutton, R. Bryan
author_sort Harsini, Faraz M.
collection PubMed
description Ferlin proteins participate in such diverse biological events as vesicle fusion in C. elegans, fusion of myoblast membranes to form myotubes, Ca(2+)-sensing during exocytosis in the hair cells of the inner ear, and Ca(2+)-dependent membrane repair in skeletal muscle cells. Ferlins are Ca(2+)-dependent, phospholipid-binding, multi-C2 domain-containing proteins with a single transmembrane helix that spans a vesicle membrane. The overall domain composition of the ferlins resembles the proteins involved in exocytosis; therefore, it is thought that they participate in membrane fusion at some level. But if ferlins do fuse membranes, then they are distinct from other known fusion proteins. Here we show that the central FerA domain from dysferlin, myoferlin, and otoferlin is a novel four-helix bundle fold with its own Ca(2+)-dependent phospholipid-binding activity. Small-angle X-ray scattering (SAXS), spectroscopic, and thermodynamic analysis of the dysferlin, myoferlin, and otoferlin FerA domains, in addition to clinically-defined dysferlin FerA mutations, suggests that the FerA domain interacts with the membrane and that this interaction is enhanced by the presence of Ca(2+).
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spelling pubmed-60533712018-07-23 FerA is a Membrane-Associating Four-Helix Bundle Domain in the Ferlin Family of Membrane-Fusion Proteins Harsini, Faraz M. Chebrolu, Sukanya Fuson, Kerry L. White, Mark A. Rice, Anne M. Sutton, R. Bryan Sci Rep Article Ferlin proteins participate in such diverse biological events as vesicle fusion in C. elegans, fusion of myoblast membranes to form myotubes, Ca(2+)-sensing during exocytosis in the hair cells of the inner ear, and Ca(2+)-dependent membrane repair in skeletal muscle cells. Ferlins are Ca(2+)-dependent, phospholipid-binding, multi-C2 domain-containing proteins with a single transmembrane helix that spans a vesicle membrane. The overall domain composition of the ferlins resembles the proteins involved in exocytosis; therefore, it is thought that they participate in membrane fusion at some level. But if ferlins do fuse membranes, then they are distinct from other known fusion proteins. Here we show that the central FerA domain from dysferlin, myoferlin, and otoferlin is a novel four-helix bundle fold with its own Ca(2+)-dependent phospholipid-binding activity. Small-angle X-ray scattering (SAXS), spectroscopic, and thermodynamic analysis of the dysferlin, myoferlin, and otoferlin FerA domains, in addition to clinically-defined dysferlin FerA mutations, suggests that the FerA domain interacts with the membrane and that this interaction is enhanced by the presence of Ca(2+). Nature Publishing Group UK 2018-07-19 /pmc/articles/PMC6053371/ /pubmed/30026467 http://dx.doi.org/10.1038/s41598-018-29184-1 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Harsini, Faraz M.
Chebrolu, Sukanya
Fuson, Kerry L.
White, Mark A.
Rice, Anne M.
Sutton, R. Bryan
FerA is a Membrane-Associating Four-Helix Bundle Domain in the Ferlin Family of Membrane-Fusion Proteins
title FerA is a Membrane-Associating Four-Helix Bundle Domain in the Ferlin Family of Membrane-Fusion Proteins
title_full FerA is a Membrane-Associating Four-Helix Bundle Domain in the Ferlin Family of Membrane-Fusion Proteins
title_fullStr FerA is a Membrane-Associating Four-Helix Bundle Domain in the Ferlin Family of Membrane-Fusion Proteins
title_full_unstemmed FerA is a Membrane-Associating Four-Helix Bundle Domain in the Ferlin Family of Membrane-Fusion Proteins
title_short FerA is a Membrane-Associating Four-Helix Bundle Domain in the Ferlin Family of Membrane-Fusion Proteins
title_sort fera is a membrane-associating four-helix bundle domain in the ferlin family of membrane-fusion proteins
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053371/
https://www.ncbi.nlm.nih.gov/pubmed/30026467
http://dx.doi.org/10.1038/s41598-018-29184-1
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