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7tdq

From Proteopedia

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Current revision

Crystal structure of KSHV KicGAS/ORF52

Structural highlights

7tdq is a 2 chain structure with sequence from Human herpesvirus 8 strain GK18. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.5Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ORF52_HHV8P Plays a role in the inhibition of host innate immune system by targeting the CGAS enzymatic activity which is the principal cytosolic DNA sensor that detects invading viral DNA (PubMed:26320998, PubMed:34015248, PubMed:34387695). Acts by inhibiting CGAS-DNA phase separation: directly binds double-stranded DNA (dsDNA) in a length dependent but sequence independent manner and is able to form DNA-induced phase separation in infected cells (PubMed:34015248, PubMed:34387695). DNA phase separation of ORF52 mediates disruption of liquid-like droplets in which CGAS is activated, thereby preventing CGAS activity (PubMed:34015248, PubMed:34387695). Targets also the HDP-RNP complex composed of DNA-PK subunits and paraspeckle proteins (PubMed:28712728). This complex is a key nuclear regulator of DNA-mediated activation of innate immune response through the cGAS-STING pathway (PubMed:28712728).^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Kaposi's sarcoma-associated herpesvirus (KSHV) inhibitor of cyclic GMP-AMP synthase (cGAS) (KicGAS) encoded by ORF52 is a conserved major tegument protein of KSHV and the first reported viral inhibitor of cGAS. In our previous study, we found that KicGAS is highly oligomerized in solution and that oligomerization is required for its cooperative DNA binding and for inhibiting DNA-induced phase separation and activation of cGAS. However, how KicGAS oligomerizes remained unclear. Here, we present the crystal structure of KicGAS at 2.5 A resolution, which reveals an "L"-shaped molecule with each arm of the L essentially formed by a single alpha helix (alpha1 and alpha2). Antiparallel dimerization of alpha2 helices from two KicGAS molecules leads to a unique "Z"-shaped dimer. Surprisingly, alpha1 is also a dimerization domain. It forms a parallel dimeric leucine zipper with the alpha1 from a neighboring dimer, leading to the formation of an infinite chain of KicGAS dimers. Residues involved in leucine zipper dimer formation are among the most conserved residues across ORF52 homologs of gammaherpesviruses. The self-oligomerization increases the valence and cooperativity of interaction with DNA. The resultant multivalent interaction is critical for the formation of liquid condensates with DNA and consequent sequestration of DNA from being sensed by cGAS, explaining its role in restricting cGAS activation. The structure presented here not only provides a mechanistic understanding of the function of KicGAS but also informs a molecular target for rational design of antivirals against KSHV and related viruses.

Structural basis of higher order oligomerization of KSHV inhibitor of cGAS.,Bhowmik D, Tian Y, Wang B, Zhu F, Yin Q Proc Natl Acad Sci U S A. 2022 Aug 16;119(33):e2200285119. doi:, 10.1073/pnas.2200285119. Epub 2022 Aug 8. PMID:35939686^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Wu JJ, Li W, Shao Y, Avey D, Fu B, Gillen J, Hand T, Ma S, Liu X, Miley W, Konrad A, Neipel F, Sturzl M, Whitby D, Li H, Zhu F. Inhibition of cGAS DNA Sensing by a Herpesvirus Virion Protein. Cell Host Microbe. 2015 Sep 9;18(3):333-44. doi: 10.1016/j.chom.2015.07.015. Epub, 2015 Aug 27. PMID:26320998 doi:http://dx.doi.org/10.1016/j.chom.2015.07.015
↑ Morchikh M, Cribier A, Raffel R, Amraoui S, Cau J, Severac D, Dubois E, Schwartz O, Bennasser Y, Benkirane M. HEXIM1 and NEAT1 Long Non-coding RNA Form a Multi-subunit Complex that Regulates DNA-Mediated Innate Immune Response. Mol Cell. 2017 Aug 3;67(3):387-399.e5. doi: 10.1016/j.molcel.2017.06.020. Epub, 2017 Jul 14. PMID:28712728 doi:http://dx.doi.org/10.1016/j.molcel.2017.06.020
↑ Xu G, Liu C, Zhou S, Li Q, Feng Y, Sun P, Feng H, Gao Y, Zhu J, Luo X, Zhan Q, Liu S, Zhu S, Deng H, Li D, Gao P. Viral tegument proteins restrict cGAS-DNA phase separation to mediate immune evasion. Mol Cell. 2021 Jul 1;81(13):2823-2837.e9. doi: 10.1016/j.molcel.2021.05.002. Epub, 2021 May 19. PMID:34015248 doi:http://dx.doi.org/10.1016/j.molcel.2021.05.002
↑ Bhowmik D, Du M, Tian Y, Ma S, Wu J, Chen Z, Yin Q, Zhu F. Cooperative DNA binding mediated by KicGAS/ORF52 oligomerization allows inhibition of DNA-induced phase separation and activation of cGAS. Nucleic Acids Res. 2021 Sep 20;49(16):9389-9403. doi: 10.1093/nar/gkab689. PMID:34387695 doi:http://dx.doi.org/10.1093/nar/gkab689
↑ Bhowmik D, Tian Y, Wang B, Zhu F, Yin Q. Structural basis of higher order oligomerization of KSHV inhibitor of cGAS. Proc Natl Acad Sci U S A. 2022 Aug 16;119(33):e2200285119. doi:, 10.1073/pnas.2200285119. Epub 2022 Aug 8. PMID:35939686 doi:http://dx.doi.org/10.1073/pnas.2200285119

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7tdq"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[7tdq]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human_herpesvirus_8_strain_GK18 Human herpesvirus 8 strain GK18]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7TDQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7TDQ FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</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=7tdq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7tdq OCA], [https://pdbe.org/7tdq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7tdq RCSB], [https://www.ebi.ac.uk/pdbsum/7tdq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7tdq ProSAT]</span></td></tr>
 </table>

7tdq

From Proteopedia

Current revision

Crystal structure of KSHV KicGAS/ORF52

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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