Critical amino acid residues for ligand binding are clustered in a predicted β-turn of the third N-terminal repeat in the integrin α4 and α5 subunits

A. Irie, T. Kamata, W. Puzon-McLaughlin, Yoshikazu Takada

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

Integrin α4β1 is a receptor for vascular cell adhesion molecule (VCAM)-1 and fibronectin (CS-1). The α4β1-ligand interaction is involved in the pathogenesis of diseases and is, therefore, a therapeutic target. Here, we identified critical residues of α4 for ligand binding using alanine-scanning mutagenesis of the previously localized putative ligand binding sites (residues 108-268). Among 43 mutations tested, mutations of Tyr187, Trp188 and Gly190 significantly inhibited cell adhesion to both VCAM-1 and CS-1. This inhibition was not due to any gross structural changes of α4β1. These critical residues are clustered in a predicted β-turn structure (residues 181-190) of the third N-terminal repeat in α4. The repeat does not contain divalent cation binding motifs. Notably, the mutations within the corresponding region of α5 significantly reduced fibronectin-α5β1 interaction. These findings suggest that the predicted β-turn structure could be ubiquitously involved in ligand binding of non-I domain integrins.

Original languageEnglish (US)
Pages (from-to)5550-5556
Number of pages7
JournalEMBO Journal
Volume14
Issue number22
StatePublished - 1995
Externally publishedYes

Fingerprint

Terminal Repeat Sequences
Integrins
Ligands
Amino Acids
Vascular Cell Adhesion Molecule-1
Mutation
Mutagenesis
Cell adhesion
Divalent Cations
Fibronectins
Cell Adhesion
Alanine
Binding Sites
Scanning
Therapeutics

Keywords

  • Fibronectin
  • Integrin
  • Ligand binding
  • Mutagenesis
  • VCAM-1

ASJC Scopus subject areas

  • Cell Biology
  • Genetics

Cite this

Critical amino acid residues for ligand binding are clustered in a predicted β-turn of the third N-terminal repeat in the integrin α4 and α5 subunits. / Irie, A.; Kamata, T.; Puzon-McLaughlin, W.; Takada, Yoshikazu.

In: EMBO Journal, Vol. 14, No. 22, 1995, p. 5550-5556.

Research output: Contribution to journalArticle

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AU - Kamata, T.

AU - Puzon-McLaughlin, W.

AU - Takada, Yoshikazu

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N2 - Integrin α4β1 is a receptor for vascular cell adhesion molecule (VCAM)-1 and fibronectin (CS-1). The α4β1-ligand interaction is involved in the pathogenesis of diseases and is, therefore, a therapeutic target. Here, we identified critical residues of α4 for ligand binding using alanine-scanning mutagenesis of the previously localized putative ligand binding sites (residues 108-268). Among 43 mutations tested, mutations of Tyr187, Trp188 and Gly190 significantly inhibited cell adhesion to both VCAM-1 and CS-1. This inhibition was not due to any gross structural changes of α4β1. These critical residues are clustered in a predicted β-turn structure (residues 181-190) of the third N-terminal repeat in α4. The repeat does not contain divalent cation binding motifs. Notably, the mutations within the corresponding region of α5 significantly reduced fibronectin-α5β1 interaction. These findings suggest that the predicted β-turn structure could be ubiquitously involved in ligand binding of non-I domain integrins.

AB - Integrin α4β1 is a receptor for vascular cell adhesion molecule (VCAM)-1 and fibronectin (CS-1). The α4β1-ligand interaction is involved in the pathogenesis of diseases and is, therefore, a therapeutic target. Here, we identified critical residues of α4 for ligand binding using alanine-scanning mutagenesis of the previously localized putative ligand binding sites (residues 108-268). Among 43 mutations tested, mutations of Tyr187, Trp188 and Gly190 significantly inhibited cell adhesion to both VCAM-1 and CS-1. This inhibition was not due to any gross structural changes of α4β1. These critical residues are clustered in a predicted β-turn structure (residues 181-190) of the third N-terminal repeat in α4. The repeat does not contain divalent cation binding motifs. Notably, the mutations within the corresponding region of α5 significantly reduced fibronectin-α5β1 interaction. These findings suggest that the predicted β-turn structure could be ubiquitously involved in ligand binding of non-I domain integrins.

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