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

Cell Reports
Florencia RosettiTanya N Mayadas

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.

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Citations

Dec 20, 2015·Immunological Reviews·Florencia Rosetti, Tanya N Mayadas
Oct 11, 2016·Experimental Cell Research·Zhenhai LiCheng Zhu
Apr 8, 2017·European Journal of Immunology·Christoph Garbers, Stefan Rose-John
Sep 29, 2017·Molecular Biology of the Cell·Yunfeng ChenCheng Zhu
Dec 16, 2016·The Journal of Immunology : Official Journal of the American Association of Immunologists·Li-Teng OngSuet-Mien Tan
Aug 9, 2018·Molecular Biology of the Cell·Sophie V PageonMaté Biro
Dec 13, 2018·Current Opinion in Rheumatology·Florencia RosettiJosé C Crispín
Aug 2, 2017·Nature Reviews. Immunology·Morgan Huse
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Jan 24, 2019·Current Opinion in Rheumatology·Florencia RosettiJosé C Crispín
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