Genetic perturbation of the putative cytoplasmic membrane-proximal salt bridge aberrantly activates α4 integrins

Yoichi Imai, Eun Jeong Park, Dan Peer, António Peixoto, Guiying Cheng, Ulrich H. Von Andrian, Christopher V. Carman, Motomu Shimaoka

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

α 4 integrins play a pivotal role in leukocyte migration and tissue-specific homing. The ability of integrins to bind ligand is dynamically regulated by activation-dependent conformational changes triggered in the cytoplasmic domain. An NMR solution structure defined a putative membrane-proximal salt bridge between the α llbβ 3 integrin cytoplasmic tails, which restrains integrins in their low-affinity state. However, the physiological importance of this salt bridge in α 4 integrin regulation remains to be elucidated. To address this question, we disrupted the salt bridge in murine germ line by mutating the conserved cytoplasmic arginine R GFFKR in α 4 integrins. In lymphocytes from knock-in mice (α 4-R/A GFFKR), α 4β 1 and α 4β 7 integrins exhibited constitu-tively up-regulated ligand binding. However, transmigration of these cells across VCAM-1 and MAdCAM-1 substrates, or across endothelial monolayers, was reduced. Perturbed detachment of the tail appeared to cause the reduced cell migration of α 4-R/A GFFKR lymphocytes. In vivo, α 4-R/A GGGKR cells exhibited increased firm adhesion to Peyer patch venules but reduced homing to the gut. Our results demonstrate that the membrane-proximal salt bridge plays a critical role in supporting proper α 4 integrin adhesive dynamics. Loss of this interaction destabilizes the nonadhesive conformation, and thereby perturbs the properly balanced cycles of adhesion and deadhesion required for efficient cell migration.

Original languageEnglish (US)
Pages (from-to)5007-5015
Number of pages9
JournalBlood
Volume112
Issue number13
DOIs
StatePublished - Dec 15 2008

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Genetic perturbation of the putative cytoplasmic membrane-proximal salt bridge aberrantly activates α<sub>4</sub> integrins'. Together they form a unique fingerprint.

Cite this