点击次数：

论文类型：期刊论文

发表时间：2013-10-08

发表刊物：PLOS ONE

收录刊物：SCIE、Scopus

卷号：8

期号：10

ISSN号：1932-6203

摘要：The Asp of the RGD motif of the ligand coordinates with the beta I domain metal ion dependent adhesion site (MIDAS) divalent cation, emphasizing the importance of the MIDAS in ligand binding. There appears to be two distinct groups of integrins that differ in their ligand binding affinity and adhesion ability. These differences may be due to a specific residue associated with the MIDAS, particularly the beta 3 residue Ala(252) and corresponding Ala in the beta 1 integrin compared to the analogous Asp residue in the beta 2 and beta 7 integrins. Interestingly, mutations in the adjacent to MIDAS (ADMIDAS) of integrins alpha 4 beta 7 and alpha L beta 2 increased the binding and adhesion abilities compared to the wild-type, while the same mutations in the alpha 2 beta 1, alpha 5 beta 1, alpha V beta 3, and alpha IIb beta 3 integrins demonstrated decreased ligand binding and adhesion. We introduced a mutation in the alpha IIb beta 3 to convert this MIDAS associated Ala252 to Asp. By combination of this mutant with mutations of one or two ADMIDAS residues, we studied the effects of this residue on ligand binding and adhesion. Then, we performed molecular dynamics simulations on the wild-type and mutant alpha IIb beta 3 integrin beta I domains, and investigated the dynamics of metal ion binding sites in different integrin-RGD complexes. We found that the tendency of calculated binding free energies was in excellent agreement with the experimental results, suggesting that the variation in this MIDAS associated residue accounts for the differences in ligand binding and adhesion among different integrins, and it accounts for the conflicting results of ADMIDAS mutations within different integrins. This study sheds more light on the role of the MIDAS associated residue pertaining to ligand binding and adhesion and suggests that this residue may play a pivotal role in integrin-mediated cell rolling and firm adhesion.