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Structural Basis for Ca2+-mediated Interaction of the Perforin C2 Domain with Lipid Membranes.

Yagi H, Conroy PJ, Leung EW, Law RH, Trapani JA, Voskoboinik I, Whisstock JC, Norton RS
J Biol Chem 290 25213-26 (2015)
Cited: 18 times
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Abstract

Natural killer cells and cytotoxic T-lymphocytes deploy perforin and granzymes to kill infected host cells. Perforin, secreted by immune cells, binds target membranes to form pores that deliver pro-apoptotic granzymes into the target cell. A crucial first step in this process is interaction of its C2 domain with target cell membranes, which is a calcium-dependent event. Some aspects of this process are understood, but many molecular details remain unclear. To address this, we investigated the mechanism of Ca(2+) and lipid binding to the C2 domain by NMR spectroscopy and x-ray crystallography. Calcium titrations, together with dodecylphosphocholine micelle experiments, confirmed that multiple Ca(2+) ions bind within the calcium-binding regions, activating perforin with respect to membrane binding. We have also determined the affinities of several of these binding sites and have shown that this interaction causes a significant structural rearrangement in CBR1. Thus, it is proposed that Ca(2+) binding at the weakest affinity site triggers changes in the C2 domain that facilitate its interaction with lipid membranes.

Articles - 4y1t mentioned but not cited (2)

  1. Yagi H, Conroy PJ, Leung EW, Law RH, Trapani JA, Voskoboinik I, Whisstock JC, Norton RS. J Biol Chem 290 25213-25226 (2015)
  2. Brennan AJ, Law RHP, Conroy PJ, Noori T, Lukoyanova N, Saibil H, Yagita H, Ciccone A, Verschoor S, Whisstock JC, Trapani JA, Voskoboinik I. Cell Death Differ 25 1517-1529 (2018)


Reviews citing this publication (4)

  1. Liu X, Lieberman J. Annu Rev Immunol 38 455-485 (2020)
  2. Spicer BA, Conroy PJ, Law RHP, Voskoboinik I, Whisstock JC. Semin Cell Dev Biol 72 117-123 (2017)
  3. Bayly-Jones C, Pang SS, Spicer BA, Whisstock JC, Dunstone MA. Front Immunol 11 581906 (2020)
  4. Johnson TK, Henstridge MA, Warr CG. Semin Cell Dev Biol 72 163-170 (2017)

Articles citing this publication (12)

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  2. Suckling RJ, Korona B, Whiteman P, Chillakuri C, Holt L, Handford PA, Lea SM. EMBO J 36 2204-2215 (2017)
  3. Xia Y, Tao H, Hu Y, Chen Q, Chen X, Xia L, Zhou L, Wang Y, Bao Y, Huang S, Ren X, Lundy SK, Dai F, Li Q, Chang AE. Oncotarget 7 60461-60474 (2016)
  4. Spicer JA, Miller CK, O'Connor PD, Jose J, Huttunen KM, Jaiswal JK, Denny WA, Akhlaghi H, Browne KA, Trapani JA. Bioorg Med Chem Lett 27 1050-1054 (2017)
  5. Trinks N, Reinhard S, Drobny M, Heilig L, Löffler J, Sauer M, Terpitz U. Commun Biol 4 1151 (2021)
  6. Bondada V, Gal J, Mashburn C, Rodgers DW, Larochelle KE, Croall DE, Geddes JW. Biochim Biophys Acta Mol Cell Res 1868 119019 (2021)
  7. Hodel AW, Rudd-Schmidt JA, Trapani JA, Voskoboinik I, Hoogenboom BW. Faraday Discuss 232 236-255 (2021)
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  9. Case Reports Zhao L, Yang H, Qu WY, Lu YJ, Feng Z. Front Oncol 13 1054175 (2023)
  10. Kwok E, Otto SC, Khuu P, Carpenter AP, Codding SJ, Reardon PN, Vanegas J, Kumar TM, Kuykendall CJ, Mehl RA, Baio J, Johnson CP. J Mol Biol 435 168193 (2023)
  11. Koga S, Takazono T, Namie H, Okuno D, Ito Y, Nakada N, Hirayama T, Takeda K, Ide S, Iwanaga N, Tashiro M, Sakamoto N, Watanabe A, Izumikawa K, Yanagihara K, Tanaka Y, Mukae H. Microbiol Spectr 12 e0361423 (2024)
  12. Naneh O, Kozorog M, Merzel F, Gilbert R, Anderluh G. Front Immunol 14 1181020 (2023)


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