7usl
Integrin alphaM/beta2 ectodomain in complex with adenylate cyclase toxin RTX751 and M1F5 Fab
Structural highlights
Disease[ITAM_HUMAN] Genetic variations in ITGAM has been associated with susceptibility to systemic lupus erythematosus type 6 (SLEB6) [MIM:609939]. Systemic lupus erythematosus (SLE) is a chronic, inflammatory and often febrile multisystemic disorder of connective tissue. It affects principally the skin, joints, kidneys and serosal membranes. It is thought to represent a failure of the regulatory mechanisms of the autoimmune system. Function[ITAM_HUMAN] Integrin alpha-M/beta-2 is implicated in various adhesive interactions of monocytes, macrophages and granulocytes as well as in mediating the uptake of complement-coated particles. It is identical with CR-3, the receptor for the iC3b fragment of the third complement component. It probably recognizes the R-G-D peptide in C3b. Integrin alpha-M/beta-2 is also a receptor for fibrinogen, factor X and ICAM1. It recognizes P1 and P2 peptides of fibrinogen gamma chain. Publication Abstract from PubMedIntegrins are ubiquitous cell-surface heterodimers that are exploited by pathogens and toxins, including leukotoxins that target beta2 integrins on phagocytes. The Bordetella adenylate cyclase toxin (ACT) uses the alphaMbeta2 integrin as a receptor, but the structural basis for integrin binding and neutralization by antibodies is poorly understood. Here, we use cryoelectron microscopy to determine a 2.7 A resolution structure of an ACT fragment bound to alphaMbeta2. This structure reveals that ACT interacts with the headpiece and calf-2 of the alphaM subunit in a non-canonical manner specific to bent, inactive alphaMbeta2. Neutralizing antibody epitopes map to ACT residues involved in alphaM binding, providing the basis for antibody-mediated attachment inhibition. Furthermore, binding to alphaMbeta2 positions the essential ACT acylation sites, which are conserved among toxins exported by type I secretion systems, at the cell membrane. These findings reveal a structural mechanism for integrin-mediated attachment and explain antibody-mediated neutralization of ACT intoxication. Structural basis for non-canonical integrin engagement by Bordetella adenylate cyclase toxin.,Goldsmith JA, DiVenere AM, Maynard JA, McLellan JS Cell Rep. 2022 Aug 16;40(7):111196. doi: 10.1016/j.celrep.2022.111196. PMID:35977491[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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