6sb5
CryoEM structure of murine perforin-2 ectodomain in a pore form
Structural highlights
FunctionMPEG1_MOUSE Plays a key role in the innate immune response following bacterial infection by polymerizing and inserting into the bacterial surface to form pores (PubMed:26402460). By breaching the surface of phagocytosed bacteria, allows antimicrobial effectors to enter the bacterial periplasmic space and degrade bacterial proteins such as superoxide dismutase sodC which contributes to bacterial virulence (PubMed:30249808). Shows antibacterial activity against a wide spectrum of Gram-positive, Gram-negative and acid-fast bacteria (PubMed:23257510, PubMed:23753625, PubMed:26402460). Reduces the viability of the intracytosolic pathogen L.monocytogenes by inhibiting acidification of the phagocytic vacuole of host cells which restricts bacterial translocation from the vacuole to the cytosol (PubMed:26831467). Required for the antibacterial activity of reactive oxygen species and nitric oxide (PubMed:26402460).[1] [2] [3] [4] [5] Publication Abstract from PubMedPerforin-2 (MPEG1) is thought to enable the killing of invading microbes engulfed by macrophages and other phagocytes, forming pores in their membranes. Loss of perforin-2 renders individual phagocytes and whole organisms significantly more susceptible to bacterial pathogens. Here, we reveal the mechanism of perforin-2 activation and activity using atomic structures of pre-pore and pore assemblies, high-speed atomic force microscopy, and functional assays. Perforin-2 forms a pre-pore assembly in which its pore-forming domain points in the opposite direction to its membrane-targeting domain. Acidification then triggers pore formation, via a 180 degrees conformational change. This novel and unexpected mechanism prevents premature bactericidal attack and may have played a key role in the evolution of all perforin family proteins. Structure and mechanism of bactericidal mammalian perforin-2, an ancient agent of innate immunity.,Ni T, Jiao F, Yu X, Aden S, Ginger L, Williams SI, Bai F, Prazak V, Karia D, Stansfeld P, Zhang P, Munson G, Anderluh G, Scheuring S, Gilbert RJC Sci Adv. 2020 Jan 29;6(5):eaax8286. doi: 10.1126/sciadv.aax8286. eCollection 2020, Jan. PMID:32064340[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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