Structural specializations of α4β7, an integrin that mediates rolling adhesion

Author:

Yu Yamei1,Zhu Jianghai1,Mi Li-Zhi1,Walz Thomas1,Sun Hao2,Chen JianFeng2,Springer Timothy A.1

Affiliation:

1. Department of Biological Chemistry and Molecular Pharmacology, Immune Disease Institute and Children’s Hospital; and Howard Hughes Medical Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02115

2. State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China

Abstract

The lymphocyte homing receptor integrin α4β7 is unusual for its ability to mediate both rolling and firm adhesion. α4β1 and α4β7 are targeted by therapeutics approved for multiple sclerosis and Crohn’s disease. Here, we show by electron microscopy and crystallography how two therapeutic Fabs, a small molecule (RO0505376), and mucosal adhesion molecule-1 (MAdCAM-1) bind α4β7. A long binding groove at the α4–β7 interface for immunoglobulin superfamily domains differs in shape from integrin pockets that bind Arg-Gly-Asp motifs. RO0505376 mimics an Ile/Leu-Asp motif in α4 ligands, and orients differently from Arg-Gly-Asp mimics. A novel auxiliary residue at the metal ion–dependent adhesion site in α4β7 is essential for binding to MAdCAM-1 in Mg2+ yet swings away when RO0505376 binds. A novel intermediate conformation of the α4β7 headpiece binds MAdCAM-1 and supports rolling adhesion. Lack of induction of the open headpiece conformation by ligand binding enables rolling adhesion to persist until integrin activation is signaled.

Publisher

Rockefeller University Press

Subject

Cell Biology

Reference68 articles.

1. Three-dimensional EM structure of the ectodomain of integrin αVβ3 in a complex with fibronectin;Adair;J. Cell Biol.,2005

2. PHENIX: building new software for automated crystallographic structure determination;Adams;Acta Crystallogr. D Biol. Crystallogr.,2002

3. Distinct but overlapping epitopes are involved in α4β7-mediated adhesion to vascular cell adhesion molecule-1, mucosal addressin-1, fibronectin, and lymphocyte aggregation;Andrew;J. Immunol.,1994

4. Focal adhesions are sites of integrin extension;Askari;J. Cell Biol.,2010

5. Electrostatics of nanosystems: application to microtubules and the ribosome;Baker;Proc. Natl. Acad. Sci. USA.,2001

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