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

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Hair-cell mechanotransduction and structure of PCDH15.(a) Schematic representation of a cochlear hair-cell stereocilia bundle highlighting the location of the tip link. (b) Mechanotransduction apparatus. PCDH15 directly conveys force to transduction channels. (c) The tip link is formed by the tip-to-tip interaction between CDH23 and PCDH15 parallel dimers25. Inset shows the location of the repeats studied here. (d) Ribbon diagram of PCDH15 EC8–10. Calcium ions in the EC8–9 linker are shown as green spheres. The calcium-free EC9–10 linker is bent. (e) Topology diagram of PCDH15 EC8–10. A typical cadherin fold with seven β strands (labeled A to G) is observed for all EC repeats. The structure shows a novel EC9–10 310 helix (blue arrow) at the EC9–10 linker and an atypical EC10 FG-α loop (red arrow). Residues that form the EC9–10 interface are highlighted with an asterisk (*).
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f1: Hair-cell mechanotransduction and structure of PCDH15.(a) Schematic representation of a cochlear hair-cell stereocilia bundle highlighting the location of the tip link. (b) Mechanotransduction apparatus. PCDH15 directly conveys force to transduction channels. (c) The tip link is formed by the tip-to-tip interaction between CDH23 and PCDH15 parallel dimers25. Inset shows the location of the repeats studied here. (d) Ribbon diagram of PCDH15 EC8–10. Calcium ions in the EC8–9 linker are shown as green spheres. The calcium-free EC9–10 linker is bent. (e) Topology diagram of PCDH15 EC8–10. A typical cadherin fold with seven β strands (labeled A to G) is observed for all EC repeats. The structure shows a novel EC9–10 310 helix (blue arrow) at the EC9–10 linker and an atypical EC10 FG-α loop (red arrow). Residues that form the EC9–10 interface are highlighted with an asterisk (*).

Mentions: In the vertebrate inner ear, sound and head movements are transformed into electrical signals by specialized mechano-receptors called hair cells123. These cells feature a bundle of actin-filled projections (stereocilia) arranged in a staircase formation that get deflected upon mechanical stimulation (Fig. 1a)4. The tip of each stereocilium is linked to its tallest neighbor by a ‘tip link' filament essential for hair-cell mechanotransduction (Fig. 1b)56789. Tip links convey force and gate inner-ear transduction channels to initiate sensory perception10.


An elastic element in the protocadherin-15 tip link of the inner ear
Hair-cell mechanotransduction and structure of PCDH15.(a) Schematic representation of a cochlear hair-cell stereocilia bundle highlighting the location of the tip link. (b) Mechanotransduction apparatus. PCDH15 directly conveys force to transduction channels. (c) The tip link is formed by the tip-to-tip interaction between CDH23 and PCDH15 parallel dimers25. Inset shows the location of the repeats studied here. (d) Ribbon diagram of PCDH15 EC8–10. Calcium ions in the EC8–9 linker are shown as green spheres. The calcium-free EC9–10 linker is bent. (e) Topology diagram of PCDH15 EC8–10. A typical cadherin fold with seven β strands (labeled A to G) is observed for all EC repeats. The structure shows a novel EC9–10 310 helix (blue arrow) at the EC9–10 linker and an atypical EC10 FG-α loop (red arrow). Residues that form the EC9–10 interface are highlighted with an asterisk (*).
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5120219&req=5

f1: Hair-cell mechanotransduction and structure of PCDH15.(a) Schematic representation of a cochlear hair-cell stereocilia bundle highlighting the location of the tip link. (b) Mechanotransduction apparatus. PCDH15 directly conveys force to transduction channels. (c) The tip link is formed by the tip-to-tip interaction between CDH23 and PCDH15 parallel dimers25. Inset shows the location of the repeats studied here. (d) Ribbon diagram of PCDH15 EC8–10. Calcium ions in the EC8–9 linker are shown as green spheres. The calcium-free EC9–10 linker is bent. (e) Topology diagram of PCDH15 EC8–10. A typical cadherin fold with seven β strands (labeled A to G) is observed for all EC repeats. The structure shows a novel EC9–10 310 helix (blue arrow) at the EC9–10 linker and an atypical EC10 FG-α loop (red arrow). Residues that form the EC9–10 interface are highlighted with an asterisk (*).
Mentions: In the vertebrate inner ear, sound and head movements are transformed into electrical signals by specialized mechano-receptors called hair cells123. These cells feature a bundle of actin-filled projections (stereocilia) arranged in a staircase formation that get deflected upon mechanical stimulation (Fig. 1a)4. The tip of each stereocilium is linked to its tallest neighbor by a ‘tip link' filament essential for hair-cell mechanotransduction (Fig. 1b)56789. Tip links convey force and gate inner-ear transduction channels to initiate sensory perception10.

View Article: PubMed Central - PubMed

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.

No MeSH data available.