This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.

Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.

2ljy

From Proteopedia

(Difference between revisions)

Jump to: navigation, search

Revision as of 20:09, 1 August 2018

Haddock model structure of the N-terminal domain dimer of HPV16 E6

Structural highlights

2ljy is a 2 chain structure with sequence from Hpv16. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	2ljx, 2ljz
Gene:	E6 (HPV16)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[VE6_HPV16] Plays a major role in the induction and maintenance of cellular transformation. Acts mainly as an oncoprotein by stimulating the destruction of many host cell key regulatory proteins. E6 associates with host E6-AP ubiquitin-protein ligase, and inactivates tumor suppressors TP53 and TP73 by targeting them to the 26S proteasome for degradation. In turn, DNA damage and chromosomal instabilities increase and lead to cell proliferation and cancer development. The complex E6/E6P targets several other substrates to degradation via the proteasome including host NFX1-91, a repressor of human telomerase reverse transcriptase (hTERT). The resulting increased expression of hTERT prevents the shortening of telomere length leading to cell immortalization. Other cellular targets including Bak, Fas-associated death domain-containing protein (FADD) and procaspase 8, are degraded by E6/E6AP causing inhibition of apoptosis. E6 also inhibits immune response by interacting with host IRF3 and TYK2. These interactions prevent IRF3 transcriptional activities and inhibit TYK2-mediated JAK-STAT activation by interferon alpha resulting in inhibition of the interferon signaling pathway.^[1] ^[2] ^[3]

Publication Abstract from PubMed

The viral oncoprotein E6 is an essential factor for cervical cancers induced by "high-risk" mucosal HPV. Among other oncogenic activities, E6 recruits the ubiquitin ligase E6AP to promote the ubiquitination and subsequent proteasomal degradation of p53. E6 is prone to self-association, which long precluded its structural analysis. Here we found that E6 specifically dimerizes through its N-terminal domain and that disruption of the dimer interface strongly increases E6 solubility. This allowed us to raise structural data covering the entire HPV16 E6 protein, including the high-resolution NMR structures of the two zinc-binding domains of E6 and a robust data-driven model structure of the N-terminal domain homodimer. Interestingly, homodimer interface mutations that disrupt E6 self-association also inactivate E6-mediated p53 degradation. These data suggest that E6 needs to self-associate via its N-terminal domain to promote the polyubiquitination of p53 by E6AP.

Solution Structure Analysis of the HPV16 E6 Oncoprotein Reveals a Self-Association Mechanism Required for E6-Mediated Degradation of p53.,Zanier K, Ould M'hamed Ould Sidi A, Boulade-Ladame C, Rybin V, Chappelle A, Atkinson A, Kieffer B, Trave G Structure. 2012 Apr 4;20(4):604-17. Epub 2012 Apr 3. PMID:22483108^[4]

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

References

↑ Klingelhutz AJ, Foster SA, McDougall JK. Telomerase activation by the E6 gene product of human papillomavirus type 16. Nature. 1996 Mar 7;380(6569):79-82. PMID:8598912 doi:http://dx.doi.org/10.1038/380079a0
↑ Ronco LV, Karpova AY, Vidal M, Howley PM. Human papillomavirus 16 E6 oncoprotein binds to interferon regulatory factor-3 and inhibits its transcriptional activity. Genes Dev. 1998 Jul 1;12(13):2061-72. PMID:9649509
↑ Li S, Labrecque S, Gauzzi MC, Cuddihy AR, Wong AH, Pellegrini S, Matlashewski GJ, Koromilas AE. The human papilloma virus (HPV)-18 E6 oncoprotein physically associates with Tyk2 and impairs Jak-STAT activation by interferon-alpha. Oncogene. 1999 Oct 14;18(42):5727-37. PMID:10523853 doi:http://dx.doi.org/10.1038/sj.onc.1202960
↑ Zanier K, Ould M'hamed Ould Sidi A, Boulade-Ladame C, Rybin V, Chappelle A, Atkinson A, Kieffer B, Trave G. Solution Structure Analysis of the HPV16 E6 Oncoprotein Reveals a Self-Association Mechanism Required for E6-Mediated Degradation of p53. Structure. 2012 Apr 4;20(4):604-17. Epub 2012 Apr 3. PMID:22483108 doi:10.1016/j.str.2012.02.001

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/2ljy"

@@ Line 1: / Line 1: @@
 ==Haddock model structure of the N-terminal domain dimer of HPV16 E6==
 <StructureSection load='2ljy' size='340' side='right' caption='[[2ljy]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
@@ Line 6: / Line 7: @@
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2ljx|2ljx]], [[2ljz|2ljz]]</td></tr>
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">E6 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=333760 HPV16])</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=2ljy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ljy OCA], [http://pdbe.org/2ljy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2ljy RCSB], [http://www.ebi.ac.uk/pdbsum/2ljy PDBsum]</span></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=2ljy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ljy OCA], [http://pdbe.org/2ljy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2ljy RCSB], [http://www.ebi.ac.uk/pdbsum/2ljy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2ljy ProSAT]</span></td></tr>
 </table>
 == Function ==

2ljy

From Proteopedia

Revision as of 20:09, 1 August 2018

Haddock model structure of the N-terminal domain dimer of HPV16 E6

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox