5t4n
From Proteopedia
Crystal Structure of Human Protocadherin-15 EC3-5 D414A Variant
Structural highlights
DiseasePCD15_HUMAN Usher syndrome type 1;Autosomal recessive non-syndromic sensorineural deafness type DFNB. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. FunctionPCD15_HUMAN Calcium-dependent cell-adhesion protein. Essential for maintenance of normal retinal and cochlear function. Publication Abstract from PubMedTip links of the inner ear are protein filaments essential for hearing and balance. Two atypical cadherins, cadherin-23 and protocadherin-15, interact in a Ca(2+)-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 Ca(2+)-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 Ca(2+)-binding linker regions: canonical EC4-5 linker binding three Ca(2+) ions, and non-canonical EC3-4 linker binding only two Ca(2+) ions. Our structures and biochemical assays reveal little difference between the D414 and D414A variants. Simulations predict that the partial Ca(2+)-free EC3-4 linker exhibits increased flexural flexibility without compromised mechanical strength, providing insight into the dynamics of tip links and other atypical cadherins. A Partial Calcium-Free Linker Confers Flexibility to Inner-Ear Protocadherin-15.,Powers RE, Gaudet R, Sotomayor M Structure. 2017 Mar 7;25(3):482-495. doi: 10.1016/j.str.2017.01.014. Epub 2017, Feb 23. PMID:28238533[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. Loading citation details.. Citations No citations found See AlsoReferences
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