|
|
| Line 1: |
Line 1: |
| | | | |
| | ==MAGI-1 PDZ1 / E6CT== | | ==MAGI-1 PDZ1 / E6CT== |
| - | <StructureSection load='2kpl' size='340' side='right' caption='[[2kpl]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''> | + | <StructureSection load='2kpl' size='340' side='right'caption='[[2kpl]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2kpl]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Hpv16 Hpv16] and [http://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2KPL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2KPL FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2kpl]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Hpv16 Hpv16] and [https://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2KPL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2KPL FirstGlance]. <br> |
| - | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2kpk|2kpk]]</td></tr> | + | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2kpk|2kpk]]</div></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BAIAP1, BAP1, MAGI1, TNRC19 ([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='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BAIAP1, BAP1, MAGI1, TNRC19 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), E6 ([https://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=2kpl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2kpl OCA], [http://pdbe.org/2kpl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2kpl RCSB], [http://www.ebi.ac.uk/pdbsum/2kpl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2kpl 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=2kpl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2kpl OCA], [https://pdbe.org/2kpl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2kpl RCSB], [https://www.ebi.ac.uk/pdbsum/2kpl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2kpl ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/MAGI1_HUMAN MAGI1_HUMAN]] May play a role as scaffolding protein at cell-cell junctions. May regulate acid-induced ASIC3 currents by modulating its expression at the cell surface (By similarity). [[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/MAGI1_HUMAN MAGI1_HUMAN]] May play a role as scaffolding protein at cell-cell junctions. May regulate acid-induced ASIC3 currents by modulating its expression at the cell surface (By similarity). [[https://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> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 21: |
Line 21: |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Guanylate kinase|Guanylate kinase]] | + | *[[Guanylate kinase 3D structures|Guanylate kinase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| Line 28: |
Line 28: |
| | [[Category: Hpv16]] | | [[Category: Hpv16]] |
| | [[Category: Human]] | | [[Category: Human]] |
| | + | [[Category: Large Structures]] |
| | [[Category: Atkinson, R A]] | | [[Category: Atkinson, R A]] |
| | [[Category: Charbonnier, S]] | | [[Category: Charbonnier, S]] |
| Structural highlights
Function
[MAGI1_HUMAN] May play a role as scaffolding protein at cell-cell junctions. May regulate acid-induced ASIC3 currents by modulating its expression at the cell surface (By similarity). [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
PDZ domains are protein interaction domains that are found in cytoplasmic proteins involved in signaling pathways and subcellular transport. Their roles in the control of cell growth, cell polarity, and cell adhesion in response to cell contact render this family of proteins targets during the development of cancer. Targeting of these network hubs by the oncoprotein E6 of "high-risk" human papillomaviruses (HPVs) serves to effect the efficient disruption of cellular processes. Using NMR, we have solved the three-dimensional solution structure of an extended construct of the second PDZ domain of MAGI-1 (MAGI-1 PDZ1) alone and bound to a peptide derived from the C-terminus of HPV16 E6, and we have characterized the changes in backbone dynamics and hydrogen bonding that occur upon binding. The binding event induces quenching of high-frequency motions in the C-terminal tail of the PDZ domain, which contacts the peptide upstream of the canonical X-[T/S]-X-[L/V] binding motif. Mutations designed in the C-terminal flanking region of the PDZ domain resulted in a significant decrease in binding affinity for E6 peptides. This detailed analysis supports the notion of a global response of the PDZ domain to the binding event, with effects propagated to distal sites, and reveals unexpected roles for the sequences flanking the canonical PDZ domain boundaries.
The Structural and Dynamic Response of MAGI-1 PDZ1 with Noncanonical Domain Boundaries to the Binding of Human Papillomavirus E6.,Charbonnier S, Nomine Y, Ramirez J, Luck K, Chapelle A, Stote RH, Trave G, Kieffer B, Atkinson RA J Mol Biol. 2011 Jan 13. PMID:21238461[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ Charbonnier S, Nomine Y, Ramirez J, Luck K, Chapelle A, Stote RH, Trave G, Kieffer B, Atkinson RA. The Structural and Dynamic Response of MAGI-1 PDZ1 with Noncanonical Domain Boundaries to the Binding of Human Papillomavirus E6. J Mol Biol. 2011 Jan 13. PMID:21238461 doi:10.1016/j.jmb.2011.01.015
|
