RT Journal Article
T1 A Lupus-Associated Mac-1 Variant Has Defects in Integrin Allostery and Interaction with Ligands under Force
A1 Azcutia Criado, Verónica
A1 Rosetti, Florencia
A1 Chen, Yunfeng
A1 Sen, Mehmet
A1 Thayer, Elizabeth
A1 Herter, Jan M.
A1 Luscinskas, Francis W.
A1 Cullere, Xavier
A1 Zhu, Cheng
A1 Mayadas, Tanya N.
AB 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.
PB Cell Press
YR 2015
FD 2015
LK https://hdl.handle.net/20.500.14352/116767
UL https://hdl.handle.net/20.500.14352/116767
LA eng
NO Rosetti, Florencia, et al. «A Lupus-Associated Mac-1 Variant Has Defects in Integrin Allostery and Interaction with Ligands under Force». Cell Reports, vol. 10, n.o 10, marzo de 2015, pp. 1655-64. DOI.org (Crossref), https://doi.org/10.1016/j.celrep.2015.02.037.
NO National Institutes of Health (US)
NO The Target Identification in Lupus Grant/Alliance for Lupus Research Foundation
NO The Consejo Nacional de Ciencia y Tecnologia and Fundacion Mexico en Harvard
NO German Research Foundation
DS Docta Complutense
RD 11 abr 2025