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====
==Cryo-EM structure of NLRP1-DPP9-VbP complex==
<StructureSection load='6x6c' size='340' side='right'caption='[[6x6c]]' scene=''>
<StructureSection load='6x6c' size='340' side='right'caption='[[6x6c]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br>
<table><tr><td colspan='2'>[[6x6c]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6X6C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6X6C FirstGlance]. <br>
</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=6x6c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6x6c OCA], [https://pdbe.org/6x6c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6x6c RCSB], [https://www.ebi.ac.uk/pdbsum/6x6c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6x6c ProSAT]</span></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.9&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GK2:[(2~{R})-1-[(2~{R})-2-azanyl-3-methyl-butanoyl]pyrrolidin-2-yl]boronic+acid'>GK2</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=6x6c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6x6c OCA], [https://pdbe.org/6x6c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6x6c RCSB], [https://www.ebi.ac.uk/pdbsum/6x6c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6x6c ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/DPP9_HUMAN DPP9_HUMAN] Idiopathic pulmonary fibrosis.
== Function ==
[https://www.uniprot.org/uniprot/DPP9_HUMAN DPP9_HUMAN] Dipeptidyl peptidase that cleaves off N-terminal dipeptides from proteins having a Pro or Ala residue at position 2.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Nucleotide-binding domain and leucine-rich repeat pyrin-domain containing protein 1 (NLRP1) is an inflammasome sensor that mediates the activation of caspase-1 to induce cytokine maturation and pyroptosis(1-4). Gain-of-function mutations of NLRP1 cause severe inflammatory diseases of the skin(4-6). NLRP1 contains a function-to-find domain that auto-proteolyses into noncovalently associated subdomains(7-9), and proteasomal degradation of the repressive N-terminal fragment of NLRP1 releases its inflammatory C-terminal fragment (NLRP1 CT)(10,11). Cytosolic dipeptidyl peptidases 8 and 9 (hereafter, DPP8/DPP9) both interact with NLRP1, and small-molecule inhibitors of DPP8/DPP9 activate NLRP1 by mechanisms that are currently unclear(10,12-14). Here we report cryo-electron microscopy structures of the human NLRP1-DPP9 complex alone and with Val-boroPro (VbP), an inhibitor of DPP8/DPP9. The structures reveal a ternary complex that comprises DPP9, full-length NLRP1 and the NLRPT CT. The binding of the NLRP1 CT to DPP9 requires full-length NLRP1, which suggests that NLRP1 activation is regulated by the ratio of NLRP1 CT to full-length NLRP1. Activation of the inflammasome by ectopic expression of the NLRP1 CT is consistently rescued by co-expression of autoproteolysis-deficient full-length NLRP1. The N terminus of the NLRP1 CT inserts into the DPP9 active site, and VbP disrupts this interaction. Thus, VbP weakens the NLRP1-DPP9 interaction and accelerates degradation of the N-terminal fragment(10) to induce inflammasome activation. Overall, these data demonstrate that DPP9 quenches low levels of NLRP1 CT and thus serves as a checkpoint for activation of the NLRP1 inflammasome.
DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation.,Hollingsworth LR, Sharif H, Griswold AR, Fontana P, Mintseris J, Dagbay KB, Paulo JA, Gygi SP, Bachovchin DA, Wu H Nature. 2021 Apr;592(7856):778-783. doi: 10.1038/s41586-021-03350-4. Epub 2021 , Mar 17. PMID:33731932<ref>PMID:33731932</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6x6c" style="background-color:#fffaf0;"></div>
==See Also==
*[[Dipeptidyl peptidase 3D structures|Dipeptidyl peptidase 3D structures]]
*[[Pyrin domain|Pyrin domain]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Z-disk]]
[[Category: Bachovchin DA]]
[[Category: Dagbay KB]]
[[Category: Fontana P]]
[[Category: Griswold AR]]
[[Category: Gygi SP]]
[[Category: Hollingsworth LR]]
[[Category: Mintseris J]]
[[Category: Paulo JA]]
[[Category: Sharif H]]
[[Category: Wu H]]
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