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

Journal Article · · Scientific Reports
ORCiD logo [1];  [2];  [1];  [1];  [3];  [3];  [4];  [3]
  1. Vanderbilt Univ. Medical Center, Nashville, TN (United States)
  2. Cornell Univ., Ithaca, NY (United States); Argonne National Lab. (ANL), Argonne, IL (United States). Northeastern Collaborative Access Team
  3. Vanderbilt Univ. Medical Center, Nashville, TN (United States); Veterans Affairs Hospital, Nashville, TN (United States)
  4. Vanderbilt Univ. Medical Center, Nashville, TN (United States); Vanderbilt Univ., Nashville, TN (United States)
+ Show Author Affiliations

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). Ca2+ is reported to promote α1I but inhibit α2I ligand binding. We co-crystallized individual I-domains with MIDAS-bound Ca2+ and report structures at 1.4 and 2.15 Å resolution, respectively. Both structures are in the “closed” ligand binding conformation where Ca2+ induces minimal global structural changes. Comparisons with Mg2+-bound structures reveal Mg2+ and Ca2+ bind α1I in a manner sufficient to promote ligand binding. In contrast, Ca2+ is displaced in the α2I domain MIDAS by 1.4 Å relative to Mg2+ 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 Ca2+ binding. A α2I E152A construct resulted in a 10,000-fold increase in Mg2+ and Ca2+ 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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
National Institute of General Medical Sciences (NIGMS); National Institutes of Health (NIH); USDOE Office of Science (SC); US Department of Veterans Affairs
Grant/Contract Number:
S10 RR029205; AC02-06CH11357; T32 HL94296–06; R01 DK18381; R01 DK069221; 5T32HL94296-06; R01DK018381; R01DK069221; I01BX002196; I01BX002025
OSTI ID:
1431362
Journal Information:
Scientific Reports, Vol. 8, Issue 1; ISSN 2045-2322
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 14 works
Citation information provided by
Web of Science

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