[PDF][PDF] A lupus-associated Mac-1 variant has defects in integrin allostery and interaction with ligands under force

F Rosetti, Y Chen, M Sen, E Thayer, V Azcutia… - Cell reports, 2015 - cell.com
F Rosetti, Y Chen, M Sen, E Thayer, V Azcutia, JM Herter, FW Luscinskas, X Cullere, C Zhu
Cell reports, 2015cell.com
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 …
Summary
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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