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The pore conformation of lymphocyte perforin
Structural highlights
Function[PERF_MOUSE] Plays a key role in secretory granule-dependent cell death, and in defense against virus-infected or neoplastic cells. Can insert into the membrane of target cells in its calcium-bound form, oligomerize and form large pores. Promotes cytolysis and apoptosis of target cells by facilitating the uptake of cytotoxic granzymes.[1] [2] [3] [4] [5] Publication Abstract from PubMedPerforin is a pore-forming protein that facilitates rapid killing of pathogen-infected or cancerous cells by the immune system. Perforin is released from cytotoxic lymphocytes, together with proapoptotic granzymes, to bind to a target cell membrane where it oligomerizes and forms pores. The pores allow granzyme entry, which rapidly triggers the apoptotic death of the target cell. Here, we present a 4-A resolution cryo-electron microscopy structure of the perforin pore, revealing previously unidentified inter- and intramolecular interactions stabilizing the assembly. During pore formation, the helix-turn-helix motif moves away from the bend in the central beta sheet to form an intermolecular contact. Cryo-electron tomography shows that prepores form on the membrane surface with minimal conformational changes. Our findings suggest the sequence of conformational changes underlying oligomerization and membrane insertion, and explain how several pathogenic mutations affect function. The pore conformation of lymphocyte perforin.,Ivanova ME, Lukoyanova N, Malhotra S, Topf M, Trapani JA, Voskoboinik I, Saibil HR Sci Adv. 2022 Feb 11;8(6):eabk3147. doi: 10.1126/sciadv.abk3147. Epub 2022 Feb, 11. PMID:35148176[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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