Regulation of Integrin αIIbβ3 Ligand Binding and Signaling by the Metal Ion Binding Sites in the β I Domain

被引:12
作者
Raborn, Joel [1 ]
Wang, Wei [1 ]
Luo, Bing-Hao [1 ]
机构
[1] Louisiana State Univ, Dept Biol Sci, Baton Rouge, LA 70803 USA
关键词
CRYSTAL-STRUCTURE; OUTSIDE-IN; EXTRACELLULAR SEGMENT; DIRECTED MUTAGENESIS; STRUCTURAL BASIS; FIRM ADHESION; ALPHA-SUBUNIT; CELL-ADHESION; AFFINITY; ACTIVATION;
D O I
10.1021/bi2000092
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The ability of alpha IIb beta 3 to bind ligands and undergo outside-in signaling is regulated by three divalent cation binding sites in the beta I domain. Specifically, the metal ion-dependent adhesion site (MIDAS) and the synergistic metal binding site (SyMBS) are thought to be required, for ligand binding due to their synergy between Ca2+ and Mg2+. The adjacent to MIDAS (ADMIDAS) is an important ligand binding regulatory site that also acts as a critical link between the beta I and hybrid domains for signaling. Mutations in this site have provided conflicting results for ligand binding and adhesion in different integrins. We have mutated the beta 3 SyMBS and ADMIDAS. The SyMBS mutant abolished ligand binding and outside in signaling, but when an activating glycosylation mutation in the alpha IIb Calf 2 domain was introduced, the ligand binding affinity and signaling were restored Thus, the SyMBS is important but not absolutely required for integrin bidirectional signaling The ADMIDAS mutants showed reduced ligand binding affinity and abolished outside-in signaling, and the activating glycosylation mutation could fully restore integrin signaling of the ADMIDAS mutant. We propose that the ADMIDAS ion stabilizes the low-affinity state when the integrin headpiece is in the closed conformation, whereas it stabilizes the high-affinity state when the headpiece is in the open conformation with the swung-out hybrid domain.
引用
收藏
页码:2084 / 2091
页数:8
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