title: Disruption of disulfide restriction at integrin knees induces activation and ligand-independent signaling of α₄β₇.
abstract: Control of integrin activation and signaling plays crucial roles in cell adhesion, spreading and migration. Here, we report that selective breakage of two conserved disulfide bonds located at the knees of integrin α4C589-C594 and β7C494-C526 activated α4β7. This activated integrin had a unique structure that was different from the typical extended conformation of active integrin. In addition, these activated α4β7 integrins spontaneously clustered on the cell membrane and triggered integrin downstream signaling independent of ligand binding. Although these disulfide bonds were not broken during α4β7 activation by inside-out signaling or Mn(2+), they could be specifically reduced by 0.1 mM dithiothreitol, a reducing strength that could be produced in vivo under certain conditions. Our findings reveal a novel mechanism of integrin activation under specific reducing conditions by which integrin can signal and promote cell spreading in the absence of ligand.
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Zhang
authors.forename: Youdong
authors.initials: Y
authors.lastname: Pan
authors.forename: Junpeng
authors.initials: J
authors.lastname: Qi
authors.forename: Jiao
authors.initials: J
authors.lastname: Yue
authors.forename: Mingbo
authors.initials: M
authors.lastname: Zhang
authors.forename: Chenqi
authors.initials: C
authors.lastname: Xu
authors.forename: Guohui
authors.initials: G
authors.lastname: Li
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Chen
mesh_terms: D000595:Amino Acid Sequence; D004220:Disulfides / Q000378:metabolism*; D006801:Humans; D039441:Integrin alpha4 / Q000737:chemistry* / Q000378:metabolism*; D039641:Integrin beta Chains / Q000737:chemistry* / Q000378:metabolism*; D008024:Ligands; D008969:Molecular Sequence Data; D011487:Protein Conformation; D016415:Sequence Alignment; D015398:Signal Transduction
chemical_list: D004220:Disulfides; D039641:Integrin beta Chains; D008024:Ligands; C091368:integrin beta7; D039441:Integrin alpha4
keywords: Disulfide-restriction; Integrin clustering; Ligand-independent signaling