title: Implications of the differing roles of the β1 and β3 transmembrane and cytoplasmic domains for integrin function.
abstract: Integrins are transmembrane receptors composed of α and β subunits. Although most integrins contain β1, canonical activation mechanisms are based on studies of the platelet integrin, αIIbβ3. Its inactive conformation is characterized by the association of the αIIb transmembrane and cytosolic domain (TM/CT) with a tilted β3 TM/CT that leads to activation when disrupted. We show significant structural differences between β1 and β3 TM/CT in bicelles. Moreover, the 'snorkeling' lysine at the TM/CT interface of β subunits, previously proposed to regulate αIIbβ3 activation by ion pairing with nearby lipids, plays opposite roles in β1 and β3 integrin function and in neither case is responsible for TM tilt. A range of affinities from almost no interaction to the relatively high avidity that characterizes αIIbβ3 is seen between various α subunits and β1 TM/CTs. The αIIbβ3-based canonical model for the roles of the TM/CT in integrin activation and function clearly does not extend to all mammalian integrins.
authors.affiliation: Department of Biochemistry, Vanderbilt University Medical Center, Nashville, United States.
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt Medical Center, Nashville, United States.
authors.forename: Sijo
authors.initials: S
authors.lastname: Mathew
authors.affiliation: Department of Biochemistry, Vanderbilt University Medical Center, Nashville, United States.
authors.forename: Jiang
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Biochemistry, Vanderbilt University Medical Center, Nashville, United States.
authors.forename: Arina
authors.initials: A
authors.lastname: Hadziselimovic
authors.affiliation: Department of Biochemistry, Vanderbilt University Medical Center, Nashville, United States.
authors.forename: Riya
authors.initials: R
authors.lastname: Palamuttam
authors.affiliation: Department of Biochemistry, Vanderbilt University Medical Center, Nashville, United States.|Division of Nephrology, Department of Medicine, Vanderbilt Medical Center, Nashville, United States.|Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, United States.|Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, United States.
authors.forename: Billy G
authors.initials: BG
authors.lastname: Hudson
authors.affiliation: Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Fässler
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt Medical Center, Nashville, United States.|Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, United States.|Veterans Affairs Hospital, Nashville, United States.|Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, United States.
authors.forename: Ambra
authors.initials: A
authors.lastname: Pozzi
authors.affiliation: Department of Biochemistry, Vanderbilt University Medical Center, Nashville, United States.
authors.forename: Charles R
authors.identifier: 0000-0003-2046-2862
authors.initials: CR
authors.lastname: Sanders
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt Medical Center, Nashville, United States.|Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, United States.|Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, United States.|Veterans Affairs Hospital, Nashville, United States.
authors.forename: Roy
authors.identifier: 0000-0003-2983-8133
authors.initials: R
authors.lastname: Zent
mesh_terms: D019943:Amino Acid Substitution; D002448:Cell Adhesion; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D039423:Integrin alpha1 / Q000737:chemistry / Q000378:metabolism*; D019012:Integrin beta1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D039661:Integrin beta3 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D040201:Platelet Membrane Glycoprotein IIb / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization
chemical_list: D039423:Integrin alpha1; D019012:Integrin beta1; D039661:Integrin beta3; D050505:Mutant Proteins; D040201:Platelet Membrane Glycoprotein IIb
keywords: biochemistry; cell biology; extracellular matrix; integrin; mouse; structural biology