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Publication Abstract from PubMed

Integrins are transmembrane cell-extracellular matrix adhesion receptors that impact many cellular functions. A subgroup of integrins contain an inserted (I) domain within the alpha-subunits (alphaI) that mediate ligand recognition where function is contingent on binding a divalent cation at the metal ion dependent adhesion site (MIDAS). Ca(2+) is reported to promote alpha1I but inhibit alpha2I ligand binding. We co-crystallized individual I-domains with MIDAS-bound Ca(2+) and report structures at 1.4 and 2.15 A resolution, respectively. Both structures are in the "closed" ligand binding conformation where Ca(2+) induces minimal global structural changes. Comparisons with Mg(2+)-bound structures reveal Mg(2+) and Ca(2+) bind alpha1I in a manner sufficient to promote ligand binding. In contrast, Ca(2+) is displaced in the alpha2I domain MIDAS by 1.4 A relative to Mg(2+) and unable to directly coordinate all MIDAS residues. We identified an E152-R192 salt bridge hypothesized to limit the flexibility of the alpha2I MIDAS, thus, reducing Ca(2+) binding. A alpha2I E152A construct resulted in a 10,000-fold increase in Mg(2+) and Ca(2+) binding affinity while increasing binding to collagen ligands 20%. These data indicate the E152-R192 salt bridge is a key distinction in the molecular mechanism of differential ion binding of these two I domains.

Salt-bridge modulates differential calcium-mediated ligand binding to integrin alpha1- and alpha2-I domains.,Brown KL, Banerjee S, Feigley A, Abe H, Blackwell TS, Pozzi A, Hudson BG, Zent R Sci Rep. 2018 Feb 13;8(1):2916. doi: 10.1038/s41598-018-21231-1. PMID:29440721^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.