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PDBsum entry 4xxw
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Cell adhesion
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PDB id
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4xxw
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References listed in PDB file
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Key reference
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Title
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Tuning inner-Ear tip-Link affinity through alternatively spliced variants of protocadherin-15.
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Authors
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Y.Narui,
M.Sotomayor.
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Ref.
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Biochemistry, 2018,
57,
1702-1710.
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PubMed id
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Abstract
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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 differences, the binding affinity between cdh23 and pcdh15(N2) is
∼6 times weaker than cdh23 and pcdh15(N1) as determined by surface plasmon
resonance analysis. Steered molecular dynamics simulations predict that the
unbinding force of the cdh23-pcdh15(N2) complex can be lower than the canonical
tip link. Our results demonstrate that alternative heterophilic tip-link
structures form stable protein-protein interactions in vitro and suggest that
homophilic PCDH15-PCDH15 tip links form through the interaction of additional EC
repeats.
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