A Lupus-Associated Mac-1 Variant Has Defects in Integrin Allostery and Interaction with Ligands under Force

Florencia Rosetti; Yunfeng Chen; Mehmet Sen; Elizabeth Thayer; Veronica Azcutia; Jan M Herter; F William Luscinskas; Xavier Cullere; Cheng Zhu; Tanya N Mayadas

doi:10.1016/j.celrep.2015.02.037

A Lupus-Associated Mac-1 Variant Has Defects in Integrin Allostery and Interaction with Ligands under Force

Cell Rep. 2015 Mar 17;10(10):1655-1664. doi: 10.1016/j.celrep.2015.02.037. Epub 2015 Mar 12.

Authors

Affiliations

¹ Department of Pathology, Center for Excellence in Vascular Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Immunology Graduate Program, Division of Medical Sciences, Harvard Graduate School of Arts and Sciences, Harvard Medical School, Boston, MA 02115, USA.
² Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA; Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA.
³ Program in Cellular and Molecular Medicine, Department of Pediatrics, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁴ Department of Pathology, Center for Excellence in Vascular Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
⁵ Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA; Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA; Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA. Electronic address: cheng.zhu@bme.gatech.edu.
⁶ Department of Pathology, Center for Excellence in Vascular Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: tmayadas@rics.bwh.harvard.edu.

Abstract

Leukocyte CD18 integrins increase their affinity for ligand by transmitting allosteric signals to and from their ligand-binding αI domain. Mechanical forces induce allosteric changes that paradoxically slow dissociation by increasing the integrin/ligand bond lifetimes, referred to as catch bonds. Mac-1 formed catch bonds with its ligands. However, a Mac-1 gene (ITGAM) coding variant (rs1143679, R77H), which is located in the β-propeller domain and is significantly associated with systemic lupus erythematosus risk, exhibits a marked impairment in 2D ligand affinity and affinity maturation under mechanical force. Targeted mutations and activating antibodies reveal that the failure in Mac-1 R77H allostery is rescued by induction of cytoplasmic tail separation and full integrin extension. These findings demonstrate roles for R77, and the β-propeller in which it resides, in force-induced allostery relay and integrin bond stabilization. Defects in these processes may have pathological consequences, as the Mac-1 R77H variant is associated with increased susceptibility to lupus.

Abstract

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