title: Cation-pi interaction regulates ligand-binding affinity and signaling of integrin alpha4beta7.
abstract: Integrin α(4)β(7) mediates rolling and firm adhesion of leucocytes, two of the critical steps in leukocyte migration and tissue specific homing. Affinity of α(4)β(7) for ligand is dynamically regulated by three interlinked metal ion-binding sites in β(7)-subunit I domain. In this study, we found that Phe185 (F185), a highly conserved aromatic residue in β(7)-subunit, links the specificity-determining loop and the synergistic metal ion-binding site (SyMBS) through cation-π interaction. Mutations of F185 that disrupted the SyMBS cation-F185 interaction led to deficient firm cell adhesion mediated by high affinity α(4)β(7), and only slightly affected rolling adhesion mediated by low affinity α(4)β(7). Disruption of SyMBS cation-F185 interaction induced partial extension of integrin ectodomain and separation of cytoplasmic tails, and impaired α(4)β(7)-mediated bidirectional signaling. In addition, loss of SyMBS cation-F185 interaction increased paxillin expression and promoted paxillin-integrin binding, leading to deficient cell spreading. Furthermore, integrin α(4)β(7)-mediated cell migration was decreased by the abolishment of SyMBS cation-F185 interaction. Thus, these findings reveal a cation-π interaction playing vital roles in the regulation of integrin affinity, signaling, and biological functions.
authors.affiliation: Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: YouDong
authors.initials: Y
authors.lastname: Pan
authors.forename: Kun
authors.initials: K
authors.lastname: Zhang
authors.forename: JunPeng
authors.initials: J
authors.lastname: Qi
authors.forename: Jiao
authors.initials: J
authors.lastname: Yue
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Springer
authors.forename: JianFeng
authors.initials: J
authors.lastname: Chen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002412:Cations / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D016023:Integrins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D036904:Leukocyte Rolling / Q000502:physiology; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D002412:Cations; D016023:Integrins; D008024:Ligands; D021122:Protein Subunits; C071777:integrin alpha4beta7