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.
Highlights
Tip link filaments convey force and gate inner-ear hair-cell transduction channels to mediate perception of sound and head movements
To understand the role of non-canonical tip-link extracellular cadherin (EC) repeats, the human protocadherin-15 EC8–10 (PCDH15 EC8–10) and the mouse EC9–10 fragments were refolded from inclusion bodies produced in Escherichia coli and used for crystallization and structural determination
The structure for mouse Pcdh[15] EC9–10 (3.35 Å, Table 1) contained 228 residues starting from Met 898 to Glu 1,125
Summary
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. The ultrastructure of tip links[6] and molecular dynamics (MD) simulations of CDH23 EC repeats with canonical calciumbinding sites[32] suggest that tip links are stiff and may not form the long-sought gating spring, yet the elasticity of the entire complex and of non-canonical EC repeats is unknown. Bound calcium ions have been shown to provide structural rigidity to cadherins[34,35,36], so the presence of unusual sites may confer flexibility and perhaps affect the tertiary and a Stereocilia Force
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
