View source for 5ug7


==Calcium bound Perforin C2 Domain - T431D==
<StructureSection load='5ug7' size='340' side='right'caption='[[5ug7]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5ug7]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UG7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5UG7 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8&#8491;</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></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=5ug7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ug7 OCA], [https://pdbe.org/5ug7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ug7 RCSB], [https://www.ebi.ac.uk/pdbsum/5ug7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ug7 ProSAT]</span></td></tr>
</table>
== Function ==
[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 ==
The pore forming, Ca(2+)-dependent protein, perforin, is essential for the function of cytotoxic lymphocytes, which are at the frontline of immune defence against pathogens and cancer. Perforin is a glycoprotein stored in the secretory granules prior to release into the immune synapse. Congenital perforin deficiency causes fatal immune dysregulation, and is associated with various haematological malignancies. At least 50% of pathological missense mutations in perforin result in protein misfolding and retention in the endoplasmic reticulum. However, the regulation of perforin proteostasis remains unexplored. Using a variety of biochemical assays that assess protein stability and acquisition of complex glycosylation, we demonstrated that the binding of Ca(2+) to the C2 domain stabilises perforin and regulates its export from the endoplasmic reticulum to the secretory granules. As perforin is a thermo-labile protein, we hypothesised that by altering its C2 domain it may be possible to improve protein stability. On the basis of the X-ray crystal structure of the perforin C2 domain, we designed a mutation (T431D) in the Ca(2+) binding loop. Mutant perforin displayed markedly enhanced thermal stability and lytic function, despite its trafficking from the endoplasmic reticulum remaining unchanged. Furthermore, by introducing the T431D mutation into A90V perforin, a pathogenic mutation, which results in protein misfolding, we corrected the A90V folding defect and completely restored perforin's cytotoxic function. These results revealed an unexpected role for the Ca(2+)-dependent C2 domain in maintaining perforin proteostasis and demonstrated the possibility of designing perforin with supra-physiological cytotoxic function through stabilisation of the C2 domain.

Perforin proteostasis is regulated through its C2 domain: supra-physiological cell death mediated by T431D-perforin.,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. 2018 Feb 7. pii: 10.1038/s41418-018-0057-z. doi:, 10.1038/s41418-018-0057-z. PMID:29416110<ref>PMID:29416110</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 5ug7" style="background-color:#fffaf0;"></div>

==See Also==
*[[Cytolysin 3D structures|Cytolysin 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Conroy PJ]]
[[Category: Law RHP]]
[[Category: Voskoboinik I]]
[[Category: Whisstock JC]]