Abstract
Tip links are protein filaments essential for hearing and balance. They convey force to and gate inner ear hair cell transduction channels to mediate sensory perception. Cadherin-23 and protocadherin-15 form tip links through a calcium-dependent heterophilic interaction of their extracellular domains, which are comprised by multiple modules termed extracellular cadherin “EC” repeats. These EC repeats are similar but not identical to each other in terms of sequence and structure, often featuring highly-conserved calcium-binding sites at the linker region between them. Recent sequence analyses and structures of cadherins revealed unusual calcium-free inter-repeat linkers in some protocahderins and other non-classical cadherins. Bound calcium ions have been shown to provide structural rigidity to cadherins, thus the presence of unusual sites may confer higher flexibility and perhaps affect the tertiary and quaternary arrangement of cadherins that harbor them. Analysis of the protocadherin-15 sequence shows unusual calcium-binding sites in some of its inter-repeat linkers. Here we present the x-ray crystal structure of repeats EC8-10 refined at 3.3 A resolution, which shows an EC9-10 calcium-free linker that alters the linear arrangement of protocadherin-15's EC repeats. We suggest that several unusual features of these repeats affect the overall elastic response of protocadherin-15 that is relevant for tip link function in sensory perception.
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