6i5p: Difference between revisions

Revision as of 23:03, 5 June 2019

Co-crystal structure of human SPOP MATH domain (E47K) and human BRD3 fragment

Structural highlights

6i5p is a 8 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Related:	6i41
Gene:	SPOP (HUMAN), BRD3, KIAA0043, RING3L (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[BRD3_HUMAN] Note=A chromosomal aberration involving BRD3 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;9)(q14;q34) with NUT which produces a BRD3-NUT fusion protein.

Function

[SPOP_HUMAN] Inhibits IPF1/PDX1 transactivation of established target promoters, such as insulin, may be by recruiting a repressor complex (By similarity). In complex with CUL3, involved in ubiquitination of BMI1, H2AFY and DAXX, and probably also in ubiquitination and proteasomal degradation of Gli2 or Gli3.^[1] ^[2] ^[3] [BRD3_HUMAN] Binds hyperacetylated chromatin and plays a role in the regulation of transcription, probably by chromatin remodeling and interaction with transcription factors. Regulates transcription by promoting the binding of the transcription factor GATA1 to its targets (By similarity). Regulates transcription of the CCND1 gene.^[4]

Publication Abstract from PubMed

BET proteins such as BRD3 are oncogenic transcriptional coactivators. SPOP binding triggers their proteasomal degradation. In both endometrial and prostate cancers, SPOP mutations occur in the MATH domain, but with opposed influence on drug susceptibility. In prostate cancer, SPOP mutations presumably cause increased BET levels, decreasing BET inhibitor drug susceptibility. As opposed, in endometrial cancer, decreased BET levels concomitant with higher BET inhibitor drug susceptibility were observed. Here, we present the to our knowledge first co-crystal structure of SPOP and a bromodomain containing protein (BRD3). Our structural and biophysical data confirm the suggested loss-of-function in prostate cancer-associated SPOP mutants and provide mechanistic explanation. As opposed to previous literature, our data on endometrial cancer-associated SPOP mutants do not show altered binding behavior compared to wild-type SPOP, indicating a more complex regulatory mechanism. SPOP mutation screening may thus be considered a valuable personalized medicine tool for effective antitumor therapy.

Structural Insights into BET Client Recognition of Endometrial and Prostate Cancer-Associated SPOP Mutants.,Ostertag MS, Hutwelker W, Plettenburg O, Sattler M, Popowicz GM J Mol Biol. 2019 Apr 23. pii: S0022-2836(19)30213-X. doi:, 10.1016/j.jmb.2019.04.017. PMID:31026449^[5]

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

References

↑ Furukawa M, He YJ, Borchers C, Xiong Y. Targeting of protein ubiquitination by BTB-Cullin 3-Roc1 ubiquitin ligases. Nat Cell Biol. 2003 Nov;5(11):1001-7. Epub 2003 Oct 5. PMID:14528312 doi:10.1038/ncb1056
↑ Hernandez-Munoz I, Lund AH, van der Stoop P, Boutsma E, Muijrers I, Verhoeven E, Nusinow DA, Panning B, Marahrens Y, van Lohuizen M. Stable X chromosome inactivation involves the PRC1 Polycomb complex and requires histone MACROH2A1 and the CULLIN3/SPOP ubiquitin E3 ligase. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7635-40. Epub 2005 May 16. PMID:15897469 doi:0408918102
↑ Kwon JE, La M, Oh KH, Oh YM, Kim GR, Seol JH, Baek SH, Chiba T, Tanaka K, Bang OS, Joe CO, Chung CH. BTB domain-containing speckle-type POZ protein (SPOP) serves as an adaptor of Daxx for ubiquitination by Cul3-based ubiquitin ligase. J Biol Chem. 2006 May 5;281(18):12664-72. Epub 2006 Mar 8. PMID:16524876 doi:10.1074/jbc.M600204200
↑ LeRoy G, Rickards B, Flint SJ. The double bromodomain proteins Brd2 and Brd3 couple histone acetylation to transcription. Mol Cell. 2008 Apr 11;30(1):51-60. doi: 10.1016/j.molcel.2008.01.018. PMID:18406326 doi:10.1016/j.molcel.2008.01.018
↑ Ostertag MS, Hutwelker W, Plettenburg O, Sattler M, Popowicz GM. Structural Insights into BET Client Recognition of Endometrial and Prostate Cancer-Associated SPOP Mutants. J Mol Biol. 2019 Apr 23. pii: S0022-2836(19)30213-X. doi:, 10.1016/j.jmb.2019.04.017. PMID:31026449 doi:https://dx.doi.org/10.1016/j.jmb.2019.04.017

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Furukawa M, He YJ, Borchers C, Xiong Y. Targeting of protein ubiquitination by BTB-Cullin 3-Roc1 ubiquitin ligases. Nat Cell Biol. 2003 Nov;5(11):1001-7. Epub 2003 Oct 5. PMID:14528312 doi:10.1038/ncb1056

[2] Hernandez-Munoz I, Lund AH, van der Stoop P, Boutsma E, Muijrers I, Verhoeven E, Nusinow DA, Panning B, Marahrens Y, van Lohuizen M. Stable X chromosome inactivation involves the PRC1 Polycomb complex and requires histone MACROH2A1 and the CULLIN3/SPOP ubiquitin E3 ligase. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7635-40. Epub 2005 May 16. PMID:15897469 doi:0408918102

[3] Kwon JE, La M, Oh KH, Oh YM, Kim GR, Seol JH, Baek SH, Chiba T, Tanaka K, Bang OS, Joe CO, Chung CH. BTB domain-containing speckle-type POZ protein (SPOP) serves as an adaptor of Daxx for ubiquitination by Cul3-based ubiquitin ligase. J Biol Chem. 2006 May 5;281(18):12664-72. Epub 2006 Mar 8. PMID:16524876 doi:10.1074/jbc.M600204200

[4] LeRoy G, Rickards B, Flint SJ. The double bromodomain proteins Brd2 and Brd3 couple histone acetylation to transcription. Mol Cell. 2008 Apr 11;30(1):51-60. doi: 10.1016/j.molcel.2008.01.018. PMID:18406326 doi:10.1016/j.molcel.2008.01.018

[5] Ostertag MS, Hutwelker W, Plettenburg O, Sattler M, Popowicz GM. Structural Insights into BET Client Recognition of Endometrial and Prostate Cancer-Associated SPOP Mutants. J Mol Biol. 2019 Apr 23. pii: S0022-2836(19)30213-X. doi:, 10.1016/j.jmb.2019.04.017. PMID:31026449 doi:https://dx.doi.org/10.1016/j.jmb.2019.04.017

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@@ Line 3: / Line 3: @@
 <StructureSection load='6i5p' size='340' side='right'caption='[[6i5p]], [[Resolution|resolution]] 1.81&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6i5p]] is a 8 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6I5P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6I5P FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6i5p]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6I5P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6I5P FirstGlance]. <br>
 </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6i41|6i41]]</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SPOP ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), BRD3, KIAA0043, RING3L ([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=6i5p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6i5p OCA], [http://pdbe.org/6i5p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6i5p RCSB], [http://www.ebi.ac.uk/pdbsum/6i5p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6i5p ProSAT]</span></td></tr>
 </table>
@@ Line 24: / Line 25: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Large Structures]]
 [[Category: Ostertag, M S]]

6i5p: Difference between revisions

Revision as of 23:03, 5 June 2019

Co-crystal structure of human SPOP MATH domain (E47K) and human BRD3 fragment

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

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