Faculty Collaboration Database

A pivotal role for a conserved bulky residue at the α1-helix of the αI integrin domain in ligand binding. J Biol Chem 2017 Dec 15;292(50):20756-20768

Date

10/29/2017

Pubmed ID

29079572

Pubmed Central ID

PMC5733610

DOI

10.1074/jbc.M117.790519

Scopus ID

2-s2.0-85038357154 (requires institutional sign-in at Scopus site)   9 Citations

Abstract

The ligand-binding βI and αI domains of integrin are the best-studied von Willebrand factor A domains undergoing significant conformational changes for affinity regulation. In both βI and αI domains, the α1- and α7-helixes work in concert to shift the metal-ion-dependent adhesion site between the resting and active states. An absolutely conserved Gly in the middle of the α1-helix of βI helps maintain the resting βI conformation, whereas the homologous position in the αI α1-helix contains a conserved Phe. A functional role of this Phe is structurally unpredictable. Using α_Lβ₂ integrin as a model, we found that the residue volume at the Phe position in the α1-helix is critical for α_Lβ₂ activation because trimming the Phe by small amino acid substitutions abolished α_Lβ₂ binding with soluble and immobilized intercellular cell adhesion molecule 1. Similar results were obtained for α_Mβ₂ integrin. Our experimental and molecular dynamics simulation data suggested that the bulky Phe acts as a pawl that stabilizes the downward ratchet-like movement of β6-α7 loop and α7-helix, required for high-affinity ligand binding. This mechanism may apply to other von Willebrand factor A domains undergoing large conformational changes. We further demonstrated that the conformational cross-talk between α_L αI and β₂ βI could be uncoupled because the β₂ extension and headpiece opening could occur independently of the αI activation. Reciprocally, the αI activation does not inevitably lead to the conformational changes of the β₂ subunit. Such loose linkage between the αI and βI is attributed to the αI flexibility and could accommodate the α_Lβ₂-mediated rolling adhesion of leukocytes.

Author List

Wang Z, Thinn AMM, Zhu J

Author

Jieqing Zhu PhD Assistant Professor, Associate Investigator in the Biochemistry department at BloodCenter of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amino Acid Sequence
Amino Acid Substitution
Binding Sites
CD11b Antigen
CD18 Antigens
Conserved Sequence
Humans
Immobilized Proteins
Integrin alpha1
Intercellular Adhesion Molecule-1
Kinetics
Ligands
Models, Molecular
Molecular Dynamics Simulation
Mutation
Phenylalanine
Protein Conformation
Protein Conformation, alpha-Helical
Protein Interaction Domains and Motifs
Protein Multimerization
Recombinant Proteins
Solubility