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

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1655-1664
Number of pages10
JournalCell Reports
Volume10
Issue number10
DOIs
StatePublished - Mar 17 2015
Externally publishedYes

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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