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

Nature Communications
Raul Araya-SecchiMarcos Sotomayor

Abstract

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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Mar 8, 2017·Experimental Cell Research·Ismail Sahin GulFrans van Roy
Dec 9, 2017·Proceedings of the National Academy of Sciences of the United States of America·Francesco GianoliAndrei S Kozlov
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Sep 24, 2020·Proceedings of the National Academy of Sciences of the United States of America·Deepanshu ChoudharyMarcos Sotomayor
Jul 19, 2019·Hearing Research·Anne G M SchilderHelen Blackshaw
Dec 12, 2018·Biophysical Journal·Pedro De-la-TorreMarcos Sotomayor

Methods Mentioned

BETA
X-ray

Related Concepts

Pcdh15 protein, mouse
PCDH15 protein, human
Metazoa
In Silico
Inner Auditory Hair Cells
Protein Conformation
Protein Precursors
Liver Cell Adhesion Molecule
Mechanotransduction, Cellular
Mouse, Swiss

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