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3nsj

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Revision as of 07:08, 12 May 2022

The X-ray crystal structure of lymphocyte perforin

Structural highlights

3nsj is a 1 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , ,
Gene:	Prf1, Pfp (LK3 transgenic mice)
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 cells and cytotoxic T lymphocytes accomplish the critically important function of killing virus-infected and neoplastic cells. They do this by releasing the pore-forming protein perforin and granzyme proteases from cytoplasmic granules into the cleft formed between the abutting killer and target cell membranes. Perforin, a 67-kilodalton multidomain protein, oligomerizes to form pores that deliver the pro-apoptopic granzymes into the cytosol of the target cell. The importance of perforin is highlighted by the fatal consequences of congenital perforin deficiency, with more than 50 different perforin mutations linked to familial haemophagocytic lymphohistiocytosis (type 2 FHL). Here we elucidate the mechanism of perforin pore formation by determining the X-ray crystal structure of monomeric murine perforin, together with a cryo-electron microscopy reconstruction of the entire perforin pore. Perforin is a thin 'key-shaped' molecule, comprising an amino-terminal membrane attack complex perforin-like (MACPF)/cholesterol dependent cytolysin (CDC) domain followed by an epidermal growth factor (EGF) domain that, together with the extreme carboxy-terminal sequence, forms a central shelf-like structure. A C-terminal C2 domain mediates initial, Ca(2+)-dependent membrane binding. Most unexpectedly, however, electron microscopy reveals that the orientation of the perforin MACPF domain in the pore is inside-out relative to the subunit arrangement in CDCs. These data reveal remarkable flexibility in the mechanism of action of the conserved MACPF/CDC fold and provide new insights into how related immune defence molecules such as complement proteins assemble into pores.

The structural basis for membrane binding and pore formation by lymphocyte perforin.,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 Nature. 2010 Nov 18;468(7322):447-51. Epub 2010 Oct 31. PMID:21037563^[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
↑ 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

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3nsj"

@@ Line 1: / Line 1: @@
 ==The X-ray crystal structure of lymphocyte perforin==
-<StructureSection load='3nsj' size='340' side='right' caption='[[3nsj]], [[Resolution|resolution]] 2.75&Aring;' scene=''>
+<StructureSection load='3nsj' size='340' side='right'caption='[[3nsj]], [[Resolution|resolution]] 2.75&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3nsj]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3NSJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3NSJ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3nsj]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3NSJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3NSJ FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Prf1, Pfp ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Prf1, Pfp ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3nsj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3nsj OCA], [http://pdbe.org/3nsj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3nsj RCSB], [http://www.ebi.ac.uk/pdbsum/3nsj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3nsj ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3nsj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3nsj OCA], [https://pdbe.org/3nsj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3nsj RCSB], [https://www.ebi.ac.uk/pdbsum/3nsj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3nsj ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/PERF_MOUSE 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.<ref>PMID:3261391</ref> <ref>PMID:8164737</ref> <ref>PMID:7526382</ref> <ref>PMID:19446473</ref> <ref>PMID:21037563</ref>
+[[https://www.uniprot.org/uniprot/PERF_MOUSE 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.<ref>PMID:3261391</ref> <ref>PMID:8164737</ref> <ref>PMID:7526382</ref> <ref>PMID:19446473</ref> <ref>PMID:21037563</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 21: / Line 21: @@
 ==See Also==
-*[[Cytolysin|Cytolysin]]
+*[[Cytolysin 3D structures|Cytolysin 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
 [[Category: Lk3 transgenic mice]]
 [[Category: Caradoc-Davies, T T]]

3nsj

From Proteopedia

Revision as of 07:08, 12 May 2022

The X-ray crystal structure of lymphocyte perforin

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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