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An elastic element in the protocadherin-15 tip link of the inner ear

Tip link filaments convey force and gate inner-ear hair-cell transduction channels to mediate perception of sound and head movements. Cadherin-23 and protocadherin-15 form tip links through a calcium-dependent interaction of their extracellular domains made of multiple extracellular cadherin (EC) re...

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Autores principales: Araya-Secchi, Raul, Neel, Brandon L., Sotomayor, Marcos
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120219/
https://www.ncbi.nlm.nih.gov/pubmed/27857071
http://dx.doi.org/10.1038/ncomms13458
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author Araya-Secchi, Raul
Neel, Brandon L.
Sotomayor, Marcos
author_facet Araya-Secchi, Raul
Neel, Brandon L.
Sotomayor, Marcos
author_sort Araya-Secchi, Raul
collection PubMed
description Tip link filaments convey force and gate inner-ear hair-cell transduction channels to mediate perception of sound and head movements. Cadherin-23 and protocadherin-15 form tip links through a calcium-dependent interaction of their extracellular domains made of multiple extracellular cadherin (EC) repeats. These repeats are structurally similar, but not identical in sequence, often featuring linkers with conserved calcium-binding sites that confer mechanical strength to them. Here we present the X-ray crystal structures of human protocadherin-15 EC8–EC10 and mouse EC9–EC10, which show an EC8–9 canonical-like calcium-binding linker, and an EC9–10 calcium-free linker that alters the linear arrangement of EC repeats. Molecular dynamics simulations and small-angle X-ray scattering experiments support this non-linear conformation. Simulations also suggest that unbending of EC9–10 confers some elasticity to otherwise rigid tip links. The new structure provides a first view of protocadherin-15's non-canonical EC linkers and suggests how they may function in inner-ear mechanotransduction, with implications for other cadherins.
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spelling pubmed-51202192017-01-13 An elastic element in the protocadherin-15 tip link of the inner ear Araya-Secchi, Raul Neel, Brandon L. Sotomayor, Marcos Nat Commun Article Tip link filaments convey force and gate inner-ear hair-cell transduction channels to mediate perception of sound and head movements. Cadherin-23 and protocadherin-15 form tip links through a calcium-dependent interaction of their extracellular domains made of multiple extracellular cadherin (EC) repeats. These repeats are structurally similar, but not identical in sequence, often featuring linkers with conserved calcium-binding sites that confer mechanical strength to them. Here we present the X-ray crystal structures of human protocadherin-15 EC8–EC10 and mouse EC9–EC10, which show an EC8–9 canonical-like calcium-binding linker, and an EC9–10 calcium-free linker that alters the linear arrangement of EC repeats. Molecular dynamics simulations and small-angle X-ray scattering experiments support this non-linear conformation. Simulations also suggest that unbending of EC9–10 confers some elasticity to otherwise rigid tip links. The new structure provides a first view of protocadherin-15's non-canonical EC linkers and suggests how they may function in inner-ear mechanotransduction, with implications for other cadherins. Nature Publishing Group 2016-11-18 /pmc/articles/PMC5120219/ /pubmed/27857071 http://dx.doi.org/10.1038/ncomms13458 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Araya-Secchi, Raul
Neel, Brandon L.
Sotomayor, Marcos
An elastic element in the protocadherin-15 tip link of the inner ear
title An elastic element in the protocadherin-15 tip link of the inner ear
title_full An elastic element in the protocadherin-15 tip link of the inner ear
title_fullStr An elastic element in the protocadherin-15 tip link of the inner ear
title_full_unstemmed An elastic element in the protocadherin-15 tip link of the inner ear
title_short An elastic element in the protocadherin-15 tip link of the inner ear
title_sort elastic element in the protocadherin-15 tip link of the inner ear
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120219/
https://www.ncbi.nlm.nih.gov/pubmed/27857071
http://dx.doi.org/10.1038/ncomms13458
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