Tuning Inner-Ear Tip-Link Affinity Through Alternatively Spliced Variants of Protocadherin-15

Biochemistry
Yoshie Narui, Marcos Sotomayor

Abstract

Human hearing relies upon the tip-to-tip interaction of two nonclassical cadherins, protocadherin-15 (PCDH15) and cadherin-23 (CDH23). Together, these proteins form a filament called the tip link that connects neighboring stereocilia of mechanosensitive hair cells. As sound waves enter the cochlea, the stereocilia deflect and tension is applied to the tip link, opening nearby transduction channels. Disruption of the tip link by loud sound or calcium chelators eliminates transduction currents and illustrates that tip-link integrity is critical for mechanosensing. Tip-link remodeling after disruption is a dynamic process, which can lead to the formation of atypical complexes that incorporate alternatively spliced variants of PCDH15. These variants are categorized into six groups (N1-N6) based upon differences in the first two extracellular cadherin (EC) repeats. Here, we characterized the two N-terminal EC repeats of all PCDH15 variants (pcdh15(N1) to pcdh15(N6)) and combined these variants to test complex formation. We solved the crystal structure of a new complex composed of CDH23 EC1-2 (cdh23) and pcdh15(N2) at 2.3 Å resolution and compared it to the canonical cdh23-pcdh15(N1) complex. While there were subtle structural differ...Continue Reading

Citations

Jun 20, 2018·Integrative and Comparative Biology·Duane R McPherson
Sep 24, 2020·Proceedings of the National Academy of Sciences of the United States of America·Deepanshu ChoudharyMarcos Sotomayor
Oct 18, 2020·Proceedings of the National Academy of Sciences of the United States of America·Mateusz SikoraAchilleas S Frangakis
Dec 12, 2018·Biophysical Journal·Pedro De-la-TorreMarcos Sotomayor

Related Concepts

Cadherins
Auditory Hair Cell
Ion Channel
Magnetic Resonance Imaging
Signal Transduction
Hexamethonium Chloride
Stereocilia
Catheter Tip
Crystal Structure
Structure

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