Salt-bridge modulates differential calcium-mediated ligand binding to integrin α1- and α2-I domains.

Brown KL, Banerjee S, Feigley A, Abe H, Blackwell TS, Pozzi A, Hudson BG, Zent R
Sci Rep. 2018 8 (1): 2916

PMID: 29440721 · PMCID: PMC5811549 · DOI:10.1038/s41598-018-21231-1

Integrins are transmembrane cell-extracellular matrix adhesion receptors that impact many cellular functions. A subgroup of integrins contain an inserted (I) domain within the α-subunits (αI) that mediate ligand recognition where function is contingent on binding a divalent cation at the metal ion dependent adhesion site (MIDAS). Ca is reported to promote α1I but inhibit α2I ligand binding. We co-crystallized individual I-domains with MIDAS-bound Ca and report structures at 1.4 and 2.15 Å resolution, respectively. Both structures are in the "closed" ligand binding conformation where Ca induces minimal global structural changes. Comparisons with Mg-bound structures reveal Mg and Ca bind α1I in a manner sufficient to promote ligand binding. In contrast, Ca is displaced in the α2I domain MIDAS by 1.4 Å relative to Mg and unable to directly coordinate all MIDAS residues. We identified an E152-R192 salt bridge hypothesized to limit the flexibility of the α2I MIDAS, thus, reducing Ca binding. A α2I E152A construct resulted in a 10,000-fold increase in Mg and Ca 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.

MeSH Terms (10)

Amino Acid Sequence Calcium Hydrogen Bonding Integrin alpha1 Integrin alpha2 Ligands Models, Molecular Protein Binding Protein Domains Thermodynamics

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