4y1s | pdb_00004y1s

Structural basis for Ca2+-mediated interaction of the perforin C2 domain with lipid membranes

Structural highlights

4y1s is a 1 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.611Å
Ligands:	CA
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

Natural killer (NK) cells and cytotoxic T-lymphocytes (CTL) deploy perforin (Prf) 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 Ca2+ and lipid binding to the C2 domain by NMR spectroscopy and X-ray crystallography. Calcium titrations, together with dodecylphosphocholine (DPC) micelle experiments confirmed that multiple Ca2+ ions bind within the calcium binding regions (CBR), activating perforin with respect to membrane binding. We have also determined the affinities of several of these binding sites and shown that this interaction causes a significant structural rearrangement in CBR1. Thus, it is proposed that Ca2+-binding at the weakest affinity site triggers changes in the C2 domain that facilitate its interaction with lipid membranes.

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. 2015 Aug 25. pii: jbc.M115.668384. PMID:26306037^[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:https://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:https://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
↑ Yagi H, Conroy PJ, Leung EW, Law RH, Trapani JA, Voskoboinik I, Whisstock JC, Norton RS. Structural Basis for Ca2+-mediated Interaction of the Perforin C2 Domain with Lipid Membranes. J Biol Chem. 2015 Aug 25. pii: jbc.M115.668384. PMID:26306037 doi:https://dx.doi.org/10.1074/jbc.M115.668384

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] 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:https://dx.doi.org/10.1038/334525a0

[2] 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:https://dx.doi.org/10.1038/369031a0

[3] 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

[4] 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

[5] 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

[6] Yagi H, Conroy PJ, Leung EW, Law RH, Trapani JA, Voskoboinik I, Whisstock JC, Norton RS. Structural Basis for Ca2+-mediated Interaction of the Perforin C2 Domain with Lipid Membranes. J Biol Chem. 2015 Aug 25. pii: jbc.M115.668384. PMID:26306037 doi:https://dx.doi.org/10.1074/jbc.M115.668384

[1]

[2]

[3]

[4]

[5]

[6]

4y1s | pdb_00004y1s

Structural basis for Ca2+-mediated interaction of the perforin C2 domain with lipid membranes

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Navigation menu

Page actions

Page actions

Personal tools

Navigation

Search

Tools