title: A Lupus-Associated Mac-1 Variant Has Defects in Integrin Allostery and Interaction with Ligands under Force.
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.
authors.affiliation: 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.
authors.forename: Florencia
authors.initials: F
authors.lastname: Rosetti
authors.affiliation: 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.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Program in Cellular and Molecular Medicine, Department of Pediatrics, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Sen
authors.affiliation: Department of Pathology, Center for Excellence in Vascular Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Thayer
authors.affiliation: Department of Pathology, Center for Excellence in Vascular Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Veronica
authors.initials: V
authors.lastname: Azcutia
authors.affiliation: Department of Pathology, Center for Excellence in Vascular Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Herter
authors.affiliation: Department of Pathology, Center for Excellence in Vascular Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: F William
authors.initials: FW
authors.lastname: Luscinskas
authors.affiliation: Department of Pathology, Center for Excellence in Vascular Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Xavier
authors.initials: X
authors.lastname: Cullere
authors.affiliation: 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.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Tanya N
authors.initials: TN
authors.lastname: Mayadas