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学科主题: 物理化学
题名: 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)
作者: Liu, Jie1;  Fu, Ting2;  Peng, Bo1;  Sun, Hao1;  Chu, HuiYing2;  Li, GuoHui2;  Chen, JianFeng1
通讯作者: 李国辉
关键词: affinity ;  cell adhesion ;  hydrophobic contacts ;  integrin ;  molecular dynamic simulation
刊名: FEBS JOURNAL
发表日期: 2014-07-01
DOI: 10.1111/febs.12829
卷: 281, 期:13, 页:2915-2926
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Life Sciences & Biomedicine
类目[WOS]: Biochemistry & Molecular Biology
研究领域[WOS]: Biochemistry & Molecular Biology
英文摘要: Integrin 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.
关键词[WOS]: ION BINDING-SITES ;  MOLECULAR-DYNAMICS ;  MONOCLONAL-ANTIBODY ;  LIGAND RECOGNITION ;  HYBRID DOMAIN ;  FIRM ADHESION ;  A-DOMAIN ;  ACTIVATION ;  ADHESIVENESS ;  MUTAGENESIS
语种: 英语
WOS记录号: WOS:000339097600003
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/144096
Appears in Collections:中国科学院大连化学物理研究所_期刊论文

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作者单位: 1.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:
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.
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