A Partial Calcium-Free Linker Confers Flexibility to Inner-Ear Protocadherin-15
Tip links of the inner ear are protein filaments essential for hearing and balance. Two atypical cadherins, cadherin-23 and protocadherin-15, interact in a Ca2+-dependent manner to form tip links. The largely unknown structure and mechanics of these proteins are integral to understanding how tip links pull on ion channels to initiate sensory perception. Protocadherin-15 has 11 extracellular cadherin (EC) repeats. Its EC3-4 linker lacks several of the canonical Ca2+-binding residues, and contains an aspartate-to-alanine polymorphism (D414A) under positive selection in East Asian populations. We present structures of protocadherin-15 EC3-5 featuring two Ca2+-binding linker regions: canonical EC4-5 linker binding three Ca2+ ions, and non-canonical EC3-4 linker binding only two Ca2+ ions. Our structures and biochemical assays reveal little difference between the D414 and D414A variants. Simulations predict that the partial Ca2+-free EC3-4 linker exhibits increased flexural flexibility without compromised mechanical strength, providing insight into the dynamics of tip links and other atypical cadherins.
- Research Organization:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Organization:
- USDOE; National Institutes of Health (NIH)
- Grant/Contract Number:
- AC02-06CH11357
- OSTI ID:
- 1424516
- Alternate ID(s):
- OSTI ID: 1357626; OSTI ID: 1397639
- Journal Information:
- Structure, Journal Name: Structure Vol. 25 Journal Issue: 3; ISSN 0969-2126
- Publisher:
- ElsevierCopyright Statement
- Country of Publication:
- United Kingdom
- Language:
- English
Web of Science
Nanomechanics of tip-link cadherins
|
journal | September 2019 |
Elasticity of individual protocadherin 15 molecules implicates tip links as the gating springs for hearing
|
journal | May 2019 |
Similar Records
Tuning Inner-Ear Tip-Link Affinity Through Alternatively Spliced Variants of Protocadherin-15
Structural Basis of Diverse Homophilic Recognition by Clustered α- and β-Protocadherins