期刊
CELL REPORTS
卷 10, 期 10, 页码 1655-1664出版社
CELL PRESS
DOI: 10.1016/j.celrep.2015.02.037
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资金
- NIH [HL065095, AI044902, T32 HL007627]
- Target Identification in Lupus Grant/Alliance for Lupus Research Foundation
- Consejo Nacional de Ciencia y Tecnologia
- Fundacion Mexico en Harvard
- German Research Foundation [HE-6810/1-1]
Leukocyte CD18 integrins increase their affinity for ligand by transmitting allosteric signals to and from their ligand-binding alpha I 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 beta-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 beta-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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