title: Modulation of integrin activation and signaling by α1/α1'-helix unbending at the junction.
abstract: How conformational signals initiated from one end of the integrin are transmitted to the other end remains elusive. At the ligand-binding βI domain, the α1/α1'-helix changes from a bent to a straightened α-helical conformation upon integrin headpiece opening. We demonstrated that a conserved glycine at the α1/α1' junction is crucial for maintaining the bent conformation of the α1/α1'-helix in the resting state. Mutations that facilitate α1/α1'-helix unbending rendered integrin constitutively active; however, mutations that block the α1/α1'-helix unbending abolished soluble ligand binding upon either outside or inside stimuli. Such mutations also blocked ligand-induced integrin extension from outside the cell, but had no effect on talin-induced integrin extension from inside the cell. In addition, integrin-mediated cell spreading, F-actin stress fiber and focal adhesion formation, and focal adhesion kinase activation were also defective in these mutant integrins, although the cells still adhered to immobilized ligands at a reduced level. Our data establish the structural role of the α1/α1' junction that allows relaxation of the α1/α1'-helix in the resting state and transmission of bidirectional conformational signals by helix unbending upon integrin activation.
authors.affiliation: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Chuanmei
authors.initials: C
authors.lastname: Zhang
authors.forename: Jiafu
authors.initials: J
authors.lastname: Liu
authors.forename: Xiuli
authors.initials: X
authors.lastname: Jiang
authors.forename: Nada
authors.initials: N
authors.lastname: Haydar
authors.forename: Can
authors.initials: C
authors.lastname: Zhang
authors.forename: Hu
authors.initials: H
authors.lastname: Shan
authors.forename: Jieqing
authors.initials: J
authors.lastname: Zhu
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D016466:CHO Cells; D002448:Cell Adhesion; D006224:Cricetinae; D003412:Cricetulus; D005340:Fibrinogen / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D039641:Integrin beta Chains / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D017433:Protein Structure, Secondary; D015398:Signal Transduction
chemical_list: D039641:Integrin beta Chains; D008024:Ligands; D005340:Fibrinogen
keywords: Integrin activation; Integrin signaling; α1/α1′-helix