The membrane-distal regions of integrin α cytoplasmic domains contribute differently to integrin inside-out activation

Sci Rep. 2018 Mar 22;8(1):5067. doi: 10.1038/s41598-018-23444-w.

Abstract

Functioning as signal receivers and transmitters, the integrin α/β cytoplasmic tails (CT) are pivotal in integrin activation and signaling. 18 α integrin subunits share a conserved membrane-proximal region but have a highly diverse membrane-distal (MD) region at their CTs. Recent studies demonstrated that the presence of α CTMD region is essential for talin-induced integrin inside-out activation. However, it remains unknown whether the non-conserved α CTMD regions differently regulate the inside-out activation of integrin. Using αIIbβ3, αLβ2, and α5β1 as model integrins and by replacing their α CTMD regions with those of α subunits that pair with β3, β2, and β1 subunits, we analyzed the function of CTMD regions of 17 α subunits in talin-mediated integrin activation. We found that the α CTMD regions play two roles on integrin, which are activation-supportive and activation-regulatory. The regulatory but not the supportive function depends on the sequence identity of α CTMD region. A membrane-proximal tyrosine residue present in the CTMD regions of a subset of α integrins was identified to negatively regulate integrin inside-out activation. Our study provides a useful resource for investigating the function of α integrin CTMD regions.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acids / chemistry
  • Animals
  • Cell Membrane / chemistry
  • Cell Membrane / genetics
  • Cytoplasm / chemistry
  • Cytoplasm / genetics
  • Cytoplasmic Structures / chemistry*
  • Cytoplasmic Structures / genetics
  • HEK293 Cells
  • Humans
  • Integrin alpha Chains / chemistry*
  • Integrin alpha Chains / classification
  • Integrin alpha Chains / genetics
  • Integrin beta Chains / chemistry*
  • Integrin beta Chains / classification
  • Integrin beta Chains / genetics
  • Mice
  • Protein Conformation
  • Protein Domains / genetics
  • Talin / chemistry
  • Talin / genetics
  • Tyrosine / chemistry

Substances

  • Amino Acids
  • Integrin alpha Chains
  • Integrin beta Chains
  • Talin
  • Tyrosine