DICP OpenIR
Subject Area物理化学
The hydrophobic contacts between the center of the beta I domain and the alpha 1/alpha 7 helices are crucial for the low-affinity state of integrin alpha(4)beta(7)
Liu, Jie1; Fu, Ting2; Peng, Bo1; Sun, Hao1; Chu, HuiYing2; Li, GuoHui2; Chen, JianFeng1; Li GH(李国辉)
KeywordAffinity Cell Adhesion Hydrophobic Contacts Integrin Molecular Dynamic Simulation
Source PublicationFEBS JOURNAL
2014-07-01
DOI10.1111/febs.12829
Volume281Issue:13Pages:2915-2926
Indexed BySCI
SubtypeArticle
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
WOS SubjectBiochemistry & Molecular Biology
WOS Research AreaBiochemistry & Molecular Biology
WOS KeywordION BINDING-SITES ; MOLECULAR-DYNAMICS ; MONOCLONAL-ANTIBODY ; LIGAND RECOGNITION ; HYBRID DOMAIN ; FIRM ADHESION ; A-DOMAIN ; ACTIVATION ; ADHESIVENESS ; MUTAGENESIS
AbstractIntegrin alpha(4)beta(7) mediates both rolling and firm adhesion of lymphocytes by modulating its affinity to the ligand: mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Integrin activation is associated with allosteric reshaping in the beta subunit I (beta I) domain. A prominently conformational change comprises displacement of the alpha 1 and alpha 7 helices in the beta I domain, suggesting that the location of these helices is important for the change in integrin affinity. In the present study, we report that the hydrophobic contacts between the center of the beta I-7 domain and the alpha 1/alpha 7 helices play critical roles in keeping alpha(4)beta(7) in a low-affinity state. Using molecular dynamics simulation, we identified nine hydrophobic residues that might be involved in the critical hydrophobic contacts maintaining integrin in a low-affinity state. Integrin beta 7I domain exhibited a lower binding free energy for ligand after disrupting these hydrophobic contacts by substituting the hydrophobic residues with Ala. Moreover, these alpha(4)beta(7) mutants not only showed high-affinity binding to soluble MAdCAM-1, but also demonstrated firm cell adhesion to immobilized MAdCAM-1 in shear flow and enhanced the strength of the alpha(4)beta(7)-MAdCAM-1 interaction. Disruption of the hydrophobic contacts also induced the active conformation of alpha(4)beta(7). Thus, the findings obtained in the present study reveal an important structural basis for the low-affinity state of integrin.
Language英语
WOS IDWOS:000339097600003
Citation statistics
Cited Times:1[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://cas-ir.dicp.ac.cn/handle/321008/144096
Collection中国科学院大连化学物理研究所
Corresponding AuthorLi GH(李国辉)
Affiliation1.Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Cell Biol, Beijing 100864, Peoples R China
2.Chinese Acad Sci, Dalian Inst Chem Phys, Lab Mol Modeling & Design, State Key Lab Mol React Dynam, Beijing 100864, Peoples R China
Recommended Citation
GB/T 7714
Liu, Jie,Fu, Ting,Peng, Bo,et al. The hydrophobic contacts between the center of the beta I domain and the alpha 1/alpha 7 helices are crucial for the low-affinity state of integrin alpha(4)beta(7)[J]. FEBS JOURNAL,2014,281(13):2915-2926.
APA Liu, Jie.,Fu, Ting.,Peng, Bo.,Sun, Hao.,Chu, HuiYing.,...&李国辉.(2014).The hydrophobic contacts between the center of the beta I domain and the alpha 1/alpha 7 helices are crucial for the low-affinity state of integrin alpha(4)beta(7).FEBS JOURNAL,281(13),2915-2926.
MLA Liu, Jie,et al."The hydrophobic contacts between the center of the beta I domain and the alpha 1/alpha 7 helices are crucial for the low-affinity state of integrin alpha(4)beta(7)".FEBS JOURNAL 281.13(2014):2915-2926.
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