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.

Highlights

  • Integrins are the principal receptors of cells for the extracellular matrix (ECM) and are heterodimeric transmembrane proteins consisting of a and b subunits (Hynes, 2002; Mathew et al, 2012a; Pozzi and Zent, 2013)

  • The goal of this study was to determine whether the canonical mechanism of integrin activation that has emerged from studies of the platelet specific aIIbb3 integrin extends to the ubiquitously expressed b1 integrins

  • We conclude that the diverse biophysical properties of b1 and b3 integrin transmembrane domain (TM) and C-terminal domain (CT) domains in combination with varying a subunit properties result in distinct mechanisms of integrin activation and function

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Summary

Introduction

Integrins are the principal receptors of cells for the extracellular matrix (ECM) and are heterodimeric transmembrane proteins consisting of a and b subunits (Hynes, 2002; Mathew et al, 2012a; Pozzi and Zent, 2013). The 18 a and 8 b integrin subunits associate non-covalently to form 24 heterodimeric integrins, which are expressed in different combinations on all cell types throughout the body. Except b4, have a large extracellular ligand-binding domain, a single transmembrane domain (TM) that spans the cell membrane and a short cytosolic C-terminal domain (CT) that regulates integrin function by binding with cytoskeletal and signaling proteins. B1 integrins, in which the b1 subunit can be paired with any one of 12 different a isoforms, are the principal integrins found in solid organs.

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