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==crystal structure of Burkholderia pseudomallei effector protein chbp in complex with nedd8==
==crystal structure of Burkholderia pseudomallei effector protein chbp in complex with nedd8==
<StructureSection load='4hcp' size='340' side='right' caption='[[4hcp]], [[Resolution|resolution]] 2.52&Aring;' scene=''>
<StructureSection load='4hcp' size='340' side='right'caption='[[4hcp]], [[Resolution|resolution]] 2.52&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4hcp]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Burps Burps] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4HCP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4HCP FirstGlance]. <br>
<table><tr><td colspan='2'>[[4hcp]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Burkholderia_pseudomallei_K96243 Burkholderia pseudomallei K96243] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4HCP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4HCP FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4hcn|4hcn]]</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=4hcp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hcp OCA], [https://pdbe.org/4hcp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4hcp RCSB], [https://www.ebi.ac.uk/pdbsum/4hcp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4hcp ProSAT]</span></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BPSS1385 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=272560 BURPS]), NEDD8 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4hcp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hcp OCA], [http://pdbe.org/4hcp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4hcp RCSB], [http://www.ebi.ac.uk/pdbsum/4hcp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4hcp ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/NEDD8_HUMAN NEDD8_HUMAN]] Ubiquitin-like protein which plays an important role in cell cycle control and embryogenesis. Covalent attachment to its substrates requires prior activation by the E1 complex UBE1C-APPBP1 and linkage to the E2 enzyme UBE2M. Attachment of NEDD8 to cullins activates their associated E3 ubiquitin ligase activity, and thus promotes polyubiquitination and proteasomal degradation of cyclins and other regulatory proteins.<ref>PMID:10318914</ref> <ref>PMID:10597293</ref> <ref>PMID:11953428</ref>
[https://www.uniprot.org/uniprot/CIF_BURPS CIF_BURPS] Protein-glutamine deamidase effector that inhibits the host cell cycle and other key cellular processes such as the actin network and programmed-cell death (PubMed:19308257, PubMed:20688984, PubMed:19225106). Acts by mediating the side chain deamidation of 'Gln-40' of host NEDD8, converting it to glutamate, thereby abolishing the activity of cullin-RING-based E3 ubiquitin-protein ligase complexes (CRL complexes) (PubMed:20688984, PubMed:21903097). Inactivation of CRL complexes prevents ubiquitination and subsequent degradation of the cyclin-dependent kinase inhibitors CDKN1A/p21 and CDKN1B/p27, leading to G1 and G2 cell cycle arrests in host cells (PubMed:19308257). Deamidation of 'Gln-40' of host NEDD8 also triggers macrophage-specific programmed cell death (PubMed:23175788). Also able to catalyze deamidation of 'Gln-40' of host ubiquitin in vitro; however, NEDD8 constitutes the preferred substrate in vivo (PubMed:20688984). Also regulates the host NF-kappa-B signaling via activation of MAPK/ERK cascade: activation of host MAPK/ERK cascade is independent of CRL complexes inhibition, suggesting that Cif has other host protein targets than NEDD8 (PubMed:28166272, PubMed:29848489).<ref>PMID:19225106</ref> <ref>PMID:19308257</ref> <ref>PMID:20688984</ref> <ref>PMID:21903097</ref> <ref>PMID:23175788</ref> <ref>PMID:28166272</ref> <ref>PMID:29848489</ref>  
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
Line 27: Line 25:
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Burps]]
[[Category: Burkholderia pseudomallei K96243]]
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Shao, F]]
[[Category: Large Structures]]
[[Category: Yao, Q]]
[[Category: Shao F]]
[[Category: Alpha/beta/alpha fold]]
[[Category: Yao Q]]
[[Category: Bacterial cytosol]]
[[Category: Deamidase]]
[[Category: Deamidation]]
[[Category: Nedd8/ubiquitin]]
[[Category: Protein binding]]

Revision as of 11:10, 3 November 2022

crystal structure of Burkholderia pseudomallei effector protein chbp in complex with nedd8crystal structure of Burkholderia pseudomallei effector protein chbp in complex with nedd8

Structural highlights

4hcp is a 2 chain structure with sequence from Burkholderia pseudomallei K96243 and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CIF_BURPS Protein-glutamine deamidase effector that inhibits the host cell cycle and other key cellular processes such as the actin network and programmed-cell death (PubMed:19308257, PubMed:20688984, PubMed:19225106). Acts by mediating the side chain deamidation of 'Gln-40' of host NEDD8, converting it to glutamate, thereby abolishing the activity of cullin-RING-based E3 ubiquitin-protein ligase complexes (CRL complexes) (PubMed:20688984, PubMed:21903097). Inactivation of CRL complexes prevents ubiquitination and subsequent degradation of the cyclin-dependent kinase inhibitors CDKN1A/p21 and CDKN1B/p27, leading to G1 and G2 cell cycle arrests in host cells (PubMed:19308257). Deamidation of 'Gln-40' of host NEDD8 also triggers macrophage-specific programmed cell death (PubMed:23175788). Also able to catalyze deamidation of 'Gln-40' of host ubiquitin in vitro; however, NEDD8 constitutes the preferred substrate in vivo (PubMed:20688984). Also regulates the host NF-kappa-B signaling via activation of MAPK/ERK cascade: activation of host MAPK/ERK cascade is independent of CRL complexes inhibition, suggesting that Cif has other host protein targets than NEDD8 (PubMed:28166272, PubMed:29848489).[1] [2] [3] [4] [5] [6] [7]

Publication Abstract from PubMed

Targeting eukaryotic proteins for deamidation modification is increasingly appreciated as a general bacterial virulence mechanism. Here, we present an atomic view of how a bacterial deamidase effector, cycle-inhibiting factor homolog in Burkholderia pseudomallei (CHBP), recognizes its host targets, ubiquitin (Ub) and Ub-like neural precursor cell expressed, developmentally down-regulated 8 (NEDD8), and catalyzes site-specific deamidation. Crystal structures of CHBP-Ub/NEDD8 complexes show that Ub and NEDD8 are similarly cradled by a large cleft in CHBP with four contacting surfaces. The pattern of Ub/NEDD8 recognition by CHBP resembles that by the E1 activation enzyme, which critically involves the Lys-11 surface in Ub/NEDD8. Close examination of the papain-like catalytic center reveals structural determinants of CHBP being an obligate glutamine deamidase. Molecular-dynamics simulation identifies Gln-31/Glu-31 of Ub/NEDD8 as one key determinant of CHBP substrate preference for NEDD8. Inspired by the idea of using the unique bacterial activity as a tool, we further discover that CHBP-catalyzed NEDD8 deamidation triggers macrophage-specific apoptosis, which predicts a previously unknown macrophage-specific proapoptotic signal that is negatively regulated by neddylation-mediated protein ubiquitination/degradation.

Structural mechanism of ubiquitin and NEDD8 deamidation catalyzed by bacterial effectors that induce macrophage-specific apoptosis.,Yao Q, Cui J, Wang J, Li T, Wan X, Luo T, Gong YN, Xu Y, Huang N, Shao F Proc Natl Acad Sci U S A. 2012 Dec 11;109(50):20395-400. doi:, 10.1073/pnas.1210831109. Epub 2012 Nov 21. PMID:23175788[8]

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

See Also

References

  1. ↑ Yao Q, Cui J, Zhu Y, Wang G, Hu L, Long C, Cao R, Liu X, Huang N, Chen S, Liu L, Shao F. A bacterial type III effector family uses the papain-like hydrolytic activity to arrest the host cell cycle. Proc Natl Acad Sci U S A. 2009 Mar 10;106(10):3716-21. Epub 2009 Feb 18. PMID:19225106
  2. ↑ Jubelin G, Chavez CV, Taieb F, Banfield MJ, Samba-Louaka A, Nobe R, Nougayrede JP, Zumbihl R, Givaudan A, Escoubas JM, Oswald E. Cycle inhibiting factors (CIFs) are a growing family of functional cyclomodulins present in invertebrate and mammal bacterial pathogens. PLoS One. 2009;4(3):e4855. doi: 10.1371/journal.pone.0004855. Epub 2009 Mar 24. PMID:19308257 doi:http://dx.doi.org/10.1371/journal.pone.0004855
  3. ↑ Cui J, Yao Q, Li S, Ding X, Lu Q, Mao H, Liu L, Zheng N, Chen S, Shao F. Glutamine deamidation and dysfunction of ubiquitin/NEDD8 induced by a bacterial effector family. Science. 2010 Sep 3;329(5996):1215-8. doi: 10.1126/science.1193844. Epub 2010 Aug, 5. PMID:20688984 doi:http://dx.doi.org/10.1126/science.1193844
  4. ↑ Boh BK, Ng MY, Leck YC, Shaw B, Long J, Sun GW, Gan YH, Searle MS, Layfield R, Hagen T. Inhibition of cullin RING ligases by cycle inhibiting factor: evidence for interference with Nedd8-induced conformational control. J Mol Biol. 2011 Oct 21;413(2):430-7. doi: 10.1016/j.jmb.2011.08.030. Epub 2011, Aug 29. PMID:21903097 doi:http://dx.doi.org/10.1016/j.jmb.2011.08.030
  5. ↑ Yao Q, Cui J, Wang J, Li T, Wan X, Luo T, Gong YN, Xu Y, Huang N, Shao F. Structural mechanism of ubiquitin and NEDD8 deamidation catalyzed by bacterial effectors that induce macrophage-specific apoptosis. Proc Natl Acad Sci U S A. 2012 Dec 11;109(50):20395-400. doi:, 10.1073/pnas.1210831109. Epub 2012 Nov 21. PMID:23175788 doi:http://dx.doi.org/10.1073/pnas.1210831109
  6. ↑ Ng MY, Wang M, Casey PJ, Gan YH, Hagen T. Activation of MAPK/ERK signaling by Burkholderia pseudomallei cycle inhibiting factor (Cif). PLoS One. 2017 Feb 6;12(2):e0171464. doi: 10.1371/journal.pone.0171464., eCollection 2017. PMID:28166272 doi:http://dx.doi.org/10.1371/journal.pone.0171464
  7. ↑ Ng MY, Gan YH, Hagen T. Characterisation of cellular effects of Burkholderia pseudomallei cycle inhibiting factor (Cif). Biol Open. 2018 Jul 16;7(7). pii: bio.028225. doi: 10.1242/bio.028225. PMID:29848489 doi:http://dx.doi.org/10.1242/bio.028225
  8. ↑ Yao Q, Cui J, Wang J, Li T, Wan X, Luo T, Gong YN, Xu Y, Huang N, Shao F. Structural mechanism of ubiquitin and NEDD8 deamidation catalyzed by bacterial effectors that induce macrophage-specific apoptosis. Proc Natl Acad Sci U S A. 2012 Dec 11;109(50):20395-400. doi:, 10.1073/pnas.1210831109. Epub 2012 Nov 21. PMID:23175788 doi:http://dx.doi.org/10.1073/pnas.1210831109

4hcp, resolution 2.52Å

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