| 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 PubMed
Perforin 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
- ↑ Shinkai Y, Takio K, Okumura K. Homology of perforin to the ninth component of complement (C9). Nature. 1988 Aug 11;334(6182):525-7. PMID:3261391 doi:http://dx.doi.org/10.1038/334525a0
- ↑ Kagi D, Ledermann B, Burki K, Seiler P, Odermatt B, Olsen KJ, Podack ER, Zinkernagel RM, Hengartner H. Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature. 1994 May 5;369(6475):31-7. PMID:8164737 doi:http://dx.doi.org/10.1038/369031a0
- ↑ Walsh CM, Matloubian M, Liu CC, Ueda R, Kurahara CG, Christensen JL, Huang MT, Young JD, Ahmed R, Clark WR. Immune function in mice lacking the perforin gene. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):10854-8. PMID:7526382
- ↑ Baran K, Dunstone M, Chia J, Ciccone A, Browne KA, Clarke CJ, Lukoyanova N, Saibil H, Whisstock JC, Voskoboinik I, Trapani JA. The molecular basis for perforin oligomerization and transmembrane pore assembly. Immunity. 2009 May;30(5):684-95. doi: 10.1016/j.immuni.2009.03.016. Epub 2009 May, 14. PMID:19446473 doi:10.1016/j.immuni.2009.03.016
- ↑ Law RH, Lukoyanova N, Voskoboinik I, Caradoc-Davies TT, Baran K, Dunstone MA, D'Angelo ME, Orlova EV, Coulibaly F, Verschoor S, Browne KA, Ciccone A, Kuiper MJ, Bird PI, Trapani JA, Saibil HR, Whisstock JC. The structural basis for membrane binding and pore formation by lymphocyte perforin. Nature. 2010 Nov 18;468(7322):447-51. Epub 2010 Oct 31. PMID:21037563 doi:10.1038/nature09518
- ↑ Ivanova ME, Lukoyanova N, Malhotra S, Topf M, Trapani JA, Voskoboinik I, Saibil HR. The pore conformation of lymphocyte perforin. Sci Adv. 2022 Feb 11;8(6):eabk3147. doi: 10.1126/sciadv.abk3147. Epub 2022 Feb, 11. PMID:35148176 doi:http://dx.doi.org/10.1126/sciadv.abk3147
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