2c6b

From Proteopedia

(Difference between revisions)

Current revision

Solution structure of the C4 zinc-finger domain of HDM2

Structural highlights

2c6b is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Solution NMR
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

MDM2_HUMAN Note=Seems to be amplified in certain tumors (including soft tissue sarcomas, osteosarcomas and gliomas). A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding.

Function

MDM2_HUMAN E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome. Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as an ubiquitin ligase E3 toward itself and ARRB1. Permits the nuclear export of p53/TP53. Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation. Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53. Also component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways. Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus. Ubiquitinates IGF1R and promotes it to proteasomal degradation.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10] ^[11]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

HDM2 is a ubiquitin E3 ligase that is a key negative regulator of the tumor suppressor p53. Here, we report the determination of the solution structure of the C4 zinc finger domain of HDM2 using multidimensional NMR. The HDM2 C4 zinc finger domain has a fold consisting of a 3(10) helix followed by four beta-strands, which shares significant structural similarity to the zinc ribbon protein family. Family based sequence analysis identified two putative binding sites, one of which resembles an RNA binding motif.

Solution structure of the C4 zinc finger domain of HDM2.,Yu GW, Allen MD, Andreeva A, Fersht AR, Bycroft M Protein Sci. 2006 Feb;15(2):384-9. Epub 2005 Dec 29. PMID:16385008^[12]

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

References

↑ Girnita L, Girnita A, Larsson O. Mdm2-dependent ubiquitination and degradation of the insulin-like growth factor 1 receptor. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8247-52. Epub 2003 Jun 23. PMID:12821780 doi:10.1073/pnas.1431613100
↑ Li M, Brooks CL, Kon N, Gu W. A dynamic role of HAUSP in the p53-Mdm2 pathway. Mol Cell. 2004 Mar 26;13(6):879-86. PMID:15053880
↑ Bernardi R, Scaglioni PP, Bergmann S, Horn HF, Vousden KH, Pandolfi PP. PML regulates p53 stability by sequestering Mdm2 to the nucleolus. Nat Cell Biol. 2004 Jul;6(7):665-72. Epub 2004 Jun 13. PMID:15195100 doi:10.1038/ncb1147
↑ Sdek P, Ying H, Chang DL, Qiu W, Zheng H, Touitou R, Allday MJ, Xiao ZX. MDM2 promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma protein. Mol Cell. 2005 Dec 9;20(5):699-708. PMID:16337594 doi:10.1016/j.molcel.2005.10.017
↑ Brady M, Vlatkovic N, Boyd MT. Regulation of p53 and MDM2 activity by MTBP. Mol Cell Biol. 2005 Jan;25(2):545-53. PMID:15632057 doi:25/2/545
↑ Stevenson LF, Sparks A, Allende-Vega N, Xirodimas DP, Lane DP, Saville MK. The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2. EMBO J. 2007 Feb 21;26(4):976-86. Epub 2007 Feb 8. PMID:17290220 doi:10.1038/sj.emboj.7601567
↑ Chen D, Zhang J, Li M, Rayburn ER, Wang H, Zhang R. RYBP stabilizes p53 by modulating MDM2. EMBO Rep. 2009 Feb;10(2):166-72. doi: 10.1038/embor.2008.231. Epub 2008 Dec 19. PMID:19098711 doi:10.1038/embor.2008.231
↑ Busso CS, Iwakuma T, Izumi T. Ubiquitination of mammalian AP endonuclease (APE1) regulated by the p53-MDM2 signaling pathway. Oncogene. 2009 Apr 2;28(13):1616-25. doi: 10.1038/onc.2009.5. Epub 2009 Feb 16. PMID:19219073 doi:10.1038/onc.2009.5
↑ Taira N, Yamamoto H, Yamaguchi T, Miki Y, Yoshida K. ATM augments nuclear stabilization of DYRK2 by inhibiting MDM2 in the apoptotic response to DNA damage. J Biol Chem. 2010 Feb 12;285(7):4909-19. doi: 10.1074/jbc.M109.042341. Epub 2009 , Dec 4. PMID:19965871 doi:10.1074/jbc.M109.042341
↑ Gilmore-Hebert M, Ramabhadran R, Stern DF. Interactions of ErbB4 and Kap1 connect the growth factor and DNA damage response pathways. Mol Cancer Res. 2010 Oct;8(10):1388-98. doi: 10.1158/1541-7786.MCR-10-0042. Epub , 2010 Sep 21. PMID:20858735 doi:10.1158/1541-7786.MCR-10-0042
↑ Fu X, Yucer N, Liu S, Li M, Yi P, Mu JJ, Yang T, Chu J, Jung SY, O'Malley BW, Gu W, Qin J, Wang Y. RFWD3-Mdm2 ubiquitin ligase complex positively regulates p53 stability in response to DNA damage. Proc Natl Acad Sci U S A. 2010 Mar 9;107(10):4579-84. doi:, 10.1073/pnas.0912094107. Epub 2010 Feb 19. PMID:20173098 doi:10.1073/pnas.0912094107
↑ Yu GW, Allen MD, Andreeva A, Fersht AR, Bycroft M. Solution structure of the C4 zinc finger domain of HDM2. Protein Sci. 2006 Feb;15(2):384-9. Epub 2005 Dec 29. PMID:16385008 doi:10.1110/ps.051927306

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 See Also
7 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2c6b"

@@ Line 1: / Line 1: @@
 ==Solution structure of the C4 zinc-finger domain of HDM2==
-<StructureSection load='2c6b' size='340' side='right'caption='[[2c6b]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
+<StructureSection load='2c6b' size='340' side='right'caption='[[2c6b]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2c6b]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2C6B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2C6B FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2c6b]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2C6B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2C6B FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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">Solution NMR</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1rv1|1rv1]], [[1t4e|1t4e]], [[1t4f|1t4f]], [[1ycr|1ycr]], [[1z1m|1z1m]], [[2c6a|2c6a]]</div></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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'>[https://proteopedia.org/fgij/fg.htm?mol=2c6b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2c6b OCA], [https://pdbe.org/2c6b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2c6b RCSB], [https://www.ebi.ac.uk/pdbsum/2c6b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2c6b ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[https://www.uniprot.org/uniprot/MDM2_HUMAN MDM2_HUMAN]] Note=Seems to be amplified in certain tumors (including soft tissue sarcomas, osteosarcomas and gliomas). A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding.
+[https://www.uniprot.org/uniprot/MDM2_HUMAN MDM2_HUMAN] Note=Seems to be amplified in certain tumors (including soft tissue sarcomas, osteosarcomas and gliomas). A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding.
 == Function ==
-[[https://www.uniprot.org/uniprot/MDM2_HUMAN MDM2_HUMAN]] E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome. Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as an ubiquitin ligase E3 toward itself and ARRB1. Permits the nuclear export of p53/TP53. Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation. Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53. Also component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways. Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus. Ubiquitinates IGF1R and promotes it to proteasomal degradation.<ref>PMID:12821780</ref> <ref>PMID:15053880</ref> <ref>PMID:15195100</ref> <ref>PMID:16337594</ref> <ref>PMID:15632057</ref> <ref>PMID:17290220</ref> <ref>PMID:19098711</ref> <ref>PMID:19219073</ref> <ref>PMID:19965871</ref> <ref>PMID:20858735</ref> <ref>PMID:20173098</ref>
+[https://www.uniprot.org/uniprot/MDM2_HUMAN MDM2_HUMAN] E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome. Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as an ubiquitin ligase E3 toward itself and ARRB1. Permits the nuclear export of p53/TP53. Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation. Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53. Also component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways. Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus. Ubiquitinates IGF1R and promotes it to proteasomal degradation.<ref>PMID:12821780</ref> <ref>PMID:15053880</ref> <ref>PMID:15195100</ref> <ref>PMID:16337594</ref> <ref>PMID:15632057</ref> <ref>PMID:17290220</ref> <ref>PMID:19098711</ref> <ref>PMID:19219073</ref> <ref>PMID:19965871</ref> <ref>PMID:20858735</ref> <ref>PMID:20173098</ref>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 38: / Line 38: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Allen, M D]]
+[[Category: Allen MD]]
-[[Category: Andreeva, A]]
+[[Category: Andreeva A]]
-[[Category: Bycroft, M]]
+[[Category: Bycroft M]]
-[[Category: Fersht, A R]]
+[[Category: Fersht AR]]
-[[Category: Yu, G W]]
+[[Category: Yu GW]]
-[[Category: Alternative splicing]]
-[[Category: Human mdm2]]
-[[Category: Ligase]]
-[[Category: Metal-binding]]
-[[Category: Nuclear protein]]
-[[Category: Phosphorylation]]
-[[Category: Proto- oncogene]]
-[[Category: Ubl conjugation pathway]]
-[[Category: Zinc]]
-[[Category: Zinc finger]]

2c6b

From Proteopedia

Current revision

Solution structure of the C4 zinc-finger domain of HDM2

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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