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| | ==Crystal structure of full-length human papillomavirus oncoprotein E6 in complex with LXXLL peptide of ubiquitin ligase E6AP at 2.55 A resolution== | | ==Crystal structure of full-length human papillomavirus oncoprotein E6 in complex with LXXLL peptide of ubiquitin ligase E6AP at 2.55 A resolution== |
| - | <StructureSection load='4giz' size='340' side='right' caption='[[4giz]], [[Resolution|resolution]] 2.55Å' scene=''> | + | <StructureSection load='4giz' size='340' side='right'caption='[[4giz]], [[Resolution|resolution]] 2.55Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4giz]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Hpv16 Hpv16] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GIZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GIZ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4giz]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12], [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Human_papillomavirus_type_16 Human papillomavirus type 16]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GIZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4GIZ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CEY:ALPHA-D-GLUCOPYRANOSYL-(1- 4)-ALPHA-D-GLUCOPYRANOSYL-(1- 4)-ALPHA-D-GLUCOPYRANOSYL-(1- 4)-ALPHA-D-GLUCOPYRANOSYL-(1- 4)-ALPHA-D-GLUCOPYRANOSYL-(1- 4)-ALPHA-D-GLUCOPYRANOSE'>CEY</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 2.55Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">malE, b4034, JW3994 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), E6 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=333760 HPV16])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=PRD_900035:alpha-maltohexaose'>PRD_900035</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=4giz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4giz OCA], [http://pdbe.org/4giz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4giz RCSB], [http://www.ebi.ac.uk/pdbsum/4giz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4giz ProSAT]</span></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=4giz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4giz OCA], [https://pdbe.org/4giz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4giz RCSB], [https://www.ebi.ac.uk/pdbsum/4giz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4giz ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Disease == |
| | + | [https://www.uniprot.org/uniprot/UBE3A_HUMAN UBE3A_HUMAN] Defects in UBE3A are a cause of Angelman syndrome (AS) [MIM:[https://omim.org/entry/105830 105830]; also known as 'happy puppet syndrome'. AS is characterized by features of severe motor and intellectual retardation, microcephaly, ataxia, frequent jerky limb movements and flapping of the arms and hands, hypotonia, hyperactivity, hypopigmentation, seizures, absence of speech, frequent smiling and episodes of paroxysmal laughter, and an unusual facies characterized by macrostomia, a large mandible and open-mouthed expression, a great propensity for protruding the tongue ('tongue thrusting'), and an occipital groove.<ref>PMID:10508479</ref> <ref>PMID:9585605</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/MALE_ECOLI MALE_ECOLI]] Involved in the high-affinity maltose membrane transport system MalEFGK. Initial receptor for the active transport of and chemotaxis toward maltooligosaccharides. [[http://www.uniprot.org/uniprot/VE6_HPV16 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.<ref>PMID:8598912</ref> <ref>PMID:9649509</ref> <ref>PMID:10523853</ref> | + | [https://www.uniprot.org/uniprot/MALE_ECOLI MALE_ECOLI] Involved in the high-affinity maltose membrane transport system MalEFGK. Initial receptor for the active transport of and chemotaxis toward maltooligosaccharides.[https://www.uniprot.org/uniprot/UBE3A_HUMAN UBE3A_HUMAN] E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and transfers it to its substrates. Several substrates have been identified including the RAD23A and RAD23B, MCM7 (which is involved in DNA replication), annexin A1, the PML tumor suppressor, and the cell cycle regulator CDKN1B. Catalyzes the high-risk human papilloma virus E6-mediated ubiquitination of p53/TP53, contributing to the neoplastic progression of cells infected by these viruses. Additionally, may function as a cellular quality control ubiquitin ligase by helping the degradation of the cytoplasmic misfolded proteins. Finally, UBE3A also promotes its own degradation in vivo.<ref>PMID:10373495</ref> <ref>PMID:19325566</ref> <ref>PMID:19233847</ref> <ref>PMID:19204938</ref> <ref>PMID:19591933</ref> <ref>PMID:22645313</ref> |
| - | <div style="background-color:#fffaf0;"> | + | |
| - | == Publication Abstract from PubMed ==
| + | |
| - | E6 viral oncoproteins are key players in epithelial tumors induced by papillomaviruses in vertebrates, including cervical cancer in humans. E6 proteins target many host proteins by specifically interacting with acidic LxxLL motifs. We solved the crystal structures of bovine (BPV1) and human (HPV16) papillomavirus E6 proteins bound to LxxLL peptides from the focal adhesion protein paxillin and the ubiquitin ligase E6AP, respectively. In both E6 proteins, two zinc domains and a linker helix form a basic-hydrophobic pocket, which captures helical LxxLL motifs in a way compatible with other interaction modes. Mutational inactivation of the LxxLL binding pocket disrupts the oncogenic activities of both E6 proteins. This work reveals the structural basis of both the multifunctionality and the oncogenicity of E6 proteins.
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| - | Structural basis for hijacking of cellular LxxLL motifs by papillomavirus E6 oncoproteins.,Zanier K, Charbonnier S, Sidi AO, McEwen AG, Ferrario MG, Poussin-Courmontagne P, Cura V, Brimer N, Babah KO, Ansari T, Muller I, Stote RH, Cavarelli J, Vande Pol S, Trave G Science. 2013 Feb 8;339(6120):694-8. doi: 10.1126/science.1229934. PMID:23393263<ref>PMID:23393263</ref>
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| - | | + | |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 4giz" style="background-color:#fffaf0;"></div>
| + | |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Hpv16]] | + | [[Category: Escherichia coli K-12]] |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Cavarelli, J]] | + | [[Category: Human papillomavirus type 16]] |
| - | [[Category: Charbonnier, S]] | + | [[Category: Large Structures]] |
| - | [[Category: Cura, V]] | + | [[Category: Cavarelli J]] |
| - | [[Category: McEwen, A G]] | + | [[Category: Charbonnier S]] |
| - | [[Category: Pol, S Vande]]
| + | [[Category: Cura V]] |
| - | [[Category: Poussin, P]] | + | [[Category: McEwen AG]] |
| - | [[Category: Trave, G]] | + | [[Category: Poussin P]] |
| - | [[Category: Zanier, K]] | + | [[Category: Trave G]] |
| - | [[Category: Viral protein]] | + | [[Category: Vande Pol S]] |
| | + | [[Category: Zanier K]] |
| Structural highlights
Disease
UBE3A_HUMAN Defects in UBE3A are a cause of Angelman syndrome (AS) [MIM:105830; also known as 'happy puppet syndrome'. AS is characterized by features of severe motor and intellectual retardation, microcephaly, ataxia, frequent jerky limb movements and flapping of the arms and hands, hypotonia, hyperactivity, hypopigmentation, seizures, absence of speech, frequent smiling and episodes of paroxysmal laughter, and an unusual facies characterized by macrostomia, a large mandible and open-mouthed expression, a great propensity for protruding the tongue ('tongue thrusting'), and an occipital groove.[1] [2]
Function
MALE_ECOLI Involved in the high-affinity maltose membrane transport system MalEFGK. Initial receptor for the active transport of and chemotaxis toward maltooligosaccharides.UBE3A_HUMAN E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and transfers it to its substrates. Several substrates have been identified including the RAD23A and RAD23B, MCM7 (which is involved in DNA replication), annexin A1, the PML tumor suppressor, and the cell cycle regulator CDKN1B. Catalyzes the high-risk human papilloma virus E6-mediated ubiquitination of p53/TP53, contributing to the neoplastic progression of cells infected by these viruses. Additionally, may function as a cellular quality control ubiquitin ligase by helping the degradation of the cytoplasmic misfolded proteins. Finally, UBE3A also promotes its own degradation in vivo.[3] [4] [5] [6] [7] [8]
References
- ↑ Scanlan MJ, Gordan JD, Williamson B, Stockert E, Bander NH, Jongeneel V, Gure AO, Jager D, Jager E, Knuth A, Chen YT, Old LJ. Antigens recognized by autologous antibody in patients with renal-cell carcinoma. Int J Cancer. 1999 Nov 12;83(4):456-64. PMID:10508479
- ↑ Malzac P, Webber H, Moncla A, Graham JM, Kukolich M, Williams C, Pagon RA, Ramsdell LA, Kishino T, Wagstaff J. Mutation analysis of UBE3A in Angelman syndrome patients. Am J Hum Genet. 1998 Jun;62(6):1353-60. PMID:9585605 doi:S0002-9297(07)62776-1
- ↑ Kumar S, Talis AL, Howley PM. Identification of HHR23A as a substrate for E6-associated protein-mediated ubiquitination. J Biol Chem. 1999 Jun 25;274(26):18785-92. PMID:10373495
- ↑ Louria-Hayon I, Alsheich-Bartok O, Levav-Cohen Y, Silberman I, Berger M, Grossman T, Matentzoglu K, Jiang YH, Muller S, Scheffner M, Haupt S, Haupt Y. E6AP promotes the degradation of the PML tumor suppressor. Cell Death Differ. 2009 Aug;16(8):1156-66. Epub 2009 Mar 27. PMID:19325566 doi:cdd200931
- ↑ Mishra A, Godavarthi SK, Maheshwari M, Goswami A, Jana NR. The ubiquitin ligase E6-AP is induced and recruited to aggresomes in response to proteasome inhibition and may be involved in the ubiquitination of Hsp70-bound misfolded proteins. J Biol Chem. 2009 Apr 17;284(16):10537-45. Epub 2009 Feb 20. PMID:19233847 doi:M806804200
- ↑ Shimoji T, Murakami K, Sugiyama Y, Matsuda M, Inubushi S, Nasu J, Shirakura M, Suzuki T, Wakita T, Kishino T, Hotta H, Miyamura T, Shoji I. Identification of annexin A1 as a novel substrate for E6AP-mediated ubiquitylation. J Cell Biochem. 2009 Apr 15;106(6):1123-35. PMID:19204938 doi:10.1002/jcb.22096
- ↑ Mishra A, Godavarthi SK, Jana NR. UBE3A/E6-AP regulates cell proliferation by promoting proteasomal degradation of p27. Neurobiol Dis. 2009 Oct;36(1):26-34. Epub 2009 Jul 8. PMID:19591933 doi:S0969-9961(09)00159-4
- ↑ Martinez-Noel G, Galligan JT, Sowa ME, Arndt V, Overton TM, Harper JW, Howley PM. Identification and proteomic analysis of distinct UBE3A/E6AP protein complexes. Mol Cell Biol. 2012 Aug;32(15):3095-106. doi: 10.1128/MCB.00201-12. Epub 2012 May, 29. PMID:22645313 doi:10.1128/MCB.00201-12
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