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The hydrophobic contacts between the center of the βI domain and the α1/α7 helices are crucial for the low‐affinity state of integrin α 4 β 7
Author(s) -
Liu Jie,
Fu Ting,
Peng Bo,
Sun Hao,
Chu HuiYing,
Li GuoHui,
Chen JianFeng
Publication year - 2014
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12829
Subject(s) - addressin , integrin , allosteric regulation , biophysics , cell adhesion , adhesion , chemistry , hydrophobic effect , ligand (biochemistry) , conformational change , stereochemistry , biochemistry , receptor , biology , organic chemistry
Integrin α 4 β 7 mediates both rolling and firm adhesion of lymphocytes by modulating its affinity to the ligand: mucosal addressin cell adhesion molecule‐1 ( MA d CAM ‐1). Integrin activation is associated with allosteric reshaping in the β subunit I (βI) domain. A prominently conformational change comprises displacement of the α1 and α7 helices in the βI 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 β 7 I domain and the α1/α7 helices play critical roles in keeping α 4 β 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 β 7 I domain exhibited a lower binding free energy for ligand after disrupting these hydrophobic contacts by substituting the hydrophobic residues with Ala. Moreover, these α 4 β 7 mutants not only showed high‐affinity binding to soluble MA d CAM ‐1, but also demonstrated firm cell adhesion to immobilized MA d CAM ‐1 in shear flow and enhanced the strength of the α 4 β 7 – MA d CAM ‐1 interaction. Disruption of the hydrophobic contacts also induced the active conformation of α 4 β 7 . Thus, the findings obtained in the present study reveal an important structural basis for the low‐affinity state of integrin.