6bxz

Crystal Structure of Pig Protocadherin-15 EC10-MAD12

spinqualitylabelsall models 6bxz, resolution 2.09Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6bxz is a 2 chain structure with sequence from Pig. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CA Gene: PCDH15 (PIG) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed The cadherin superfamily of proteins is defined by the presence of extracellular cadherin (EC) "repeats" that engage in protein-protein interactions to mediate cell-cell adhesion, cell signaling, and mechanotransduction. The extracellular domains of nonclassical cadherins often have a large number of EC repeats along with other subdomains of various folds. Protocadherin-15 (PCDH15), a protein component of the inner-ear tip link filament essential for mechanotransduction, has 11 EC repeats and a membrane adjacent domain (MAD12) of atypical fold. Here we report the crystal structure of a pig PCDH15 fragment including EC10, EC11, and MAD12 in a parallel dimeric arrangement. MAD12 has a unique molecular architecture and folds as a ferredoxin-like domain similar to that found in the nucleoporin protein Nup54. Analytical ultracentrifugation experiments along with size-exclusion chromatography coupled to multiangle laser light scattering and small-angle x-ray scattering corroborate the crystallographic dimer and show that MAD12 induces parallel dimerization of PCDH15 near its membrane insertion point. In addition, steered molecular dynamics simulations suggest that MAD12 is mechanically weak and may unfold before tip-link rupture. Sequence analyses and structural modeling predict the existence of similar domains in cadherin-23, protocadherin-24, and the "giant" FAT and CELSR cadherins, indicating that some of them may also exhibit MAD-induced parallel dimerization. A Mechanically Weak Extracellular Membrane-Adjacent Domain Induces Dimerization of Protocadherin-15.,De-la-Torre P, Choudhary D, Araya-Secchi R, Narui Y, Sotomayor M Biophys J. 2018 Dec 18;115(12):2368-2385. doi: 10.1016/j.bpj.2018.11.010. Epub, 2018 Nov 16. PMID:30527337 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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