6BXZ

Crystal Structure of Pig Protocadherin-15 EC10-MAD12

Summary for 6BXZ

• Entry DOI: 10.2210/pdb6bxz/pdb
• Descriptor: Protocadherin related 15, CALCIUM ION (3 entities in total)
• Functional Keywords: hearing, mechanotransduction, adhesion, calcium-binding protein, cell adhesion
• Biological source: Sus scrofa (Pig)
• Total number of polymer chains: 2
• Total formula weight: 80265.16

Authors

De-la-Torre, P.,Araya-Secchi, R.,Choudhary, D.,Sotomayor, M. (deposition date: 2017-12-19, release date: 2018-11-28, Last modification date: 2023-10-04)

Primary citation

De-la-Torre, P.,Choudhary, D.,Araya-Secchi, R.,Narui, Y.,Sotomayor, M.
A Mechanically Weak Extracellular Membrane-Adjacent Domain Induces Dimerization of Protocadherin-15.
Biophys. J., 115:2368-2385, 2018

PubMed Abstract: 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.

PubMed: 30527337
DOI: 10.1016/j.bpj.2018.11.010

Experimental method

X-RAY DIFFRACTION (2.09 Å)