6m14: Difference between revisions

Latest revision as of 15:10, 29 November 2023

Crystal Structure of the BARD1 BRCT Mutant

Structural highlights

6m14 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.8800184Å
Ligands:	SO4
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

BARD1_HUMAN Probable E3 ubiquitin-protein ligase. The BRCA1-BARD1 heterodimer specifically mediates the formation of 'Lys-6'-linked polyubiquitin chains and coordinates a diverse range of cellular pathways such as DNA damage repair, ubiquitination and transcriptional regulation to maintain genomic stability. Plays a central role in the control of the cell cycle in response to DNA damage. Acts by mediating ubiquitin E3 ligase activity that is required for its tumor suppressor function. Also forms a heterodimer with CSTF1/CSTF-50 to modulate mRNA processing and RNAP II stability by inhibiting pre-mRNA 3' cleavage.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

OLA1 is a P-loop ATPase, implicated in centrosome duplication through the interactions with tumor suppressors BRCA1 and BARD1. Disruption of the interaction of OLA1 with BARD1 results in centrosome amplification. However, the molecular interplay and mechanism of the OLA1-BARD1 complex remain elusive. Here, we use a battery of biophysical, biochemical, and structural analyses to elucidate the molecular basis of the OLA1-BARD1 interaction. Our structural and enzyme kinetics analyses show this nucleotide-dependent interaction enhances the ATPase activity of OLA1 by increasing the turnover number (kcat). Unlike canonical GTPase activating proteins that act directly on the catalytic G domain, the BARD1 BRCT domain binds to the OLA1 TGS domain via a highly conserved BUDR motif. A cancer related mutation V695L on BARD1 is known to associate with centrosome abnormality. The V695L mutation reduces the BARD1 BRCT-mediated activation of OLA1. Crystallographic snapshot of the BRCT V695L mutant at 1.88 A reveals this mutation perturbs the OLA1 binding site, resulting in reduced interaction. Altogether, our findings suggest the BARD1 BRCT domain serves as an ATPase activating protein to control OLA1 allosterically.

BARD1 is an ATPase activating protein for OLA1.,Chen T, Yeh HW, Chen PP, Huang WT, Wu CY, Liao TC, Lin SL, Chen YY, Lin KT, Hsu SD, Cheng HC Biochim Biophys Acta Gen Subj. 2022 Feb 5;1866(5):130099. doi:, 10.1016/j.bbagen.2022.130099. PMID:35134491^[5]

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

References

↑ Kleiman FE, Manley JL. Functional interaction of BRCA1-associated BARD1 with polyadenylation factor CstF-50. Science. 1999 Sep 3;285(5433):1576-9. PMID:10477523
↑ Wu-Baer F, Lagrazon K, Yuan W, Baer R. The BRCA1/BARD1 heterodimer assembles polyubiquitin chains through an unconventional linkage involving lysine residue K6 of ubiquitin. J Biol Chem. 2003 Sep 12;278(37):34743-6. Epub 2003 Jul 30. PMID:12890688 doi:10.1074/jbc.C300249200
↑ Morris JR, Solomon E. BRCA1 : BARD1 induces the formation of conjugated ubiquitin structures, dependent on K6 of ubiquitin, in cells during DNA replication and repair. Hum Mol Genet. 2004 Apr 15;13(8):807-17. Epub 2004 Feb 19. PMID:14976165 doi:10.1093/hmg/ddh095
↑ Wu-Baer F, Ludwig T, Baer R. The UBXN1 protein associates with autoubiquitinated forms of the BRCA1 tumor suppressor and inhibits its enzymatic function. Mol Cell Biol. 2010 Jun;30(11):2787-98. doi: 10.1128/MCB.01056-09. Epub 2010 Mar , 29. PMID:20351172 doi:10.1128/MCB.01056-09
↑ Chen T, Yeh HW, Chen PP, Huang WT, Wu CY, Liao TC, Lin SL, Chen YY, Lin KT, Hsu SD, Cheng HC. BARD1 is an ATPase activating protein for OLA1. Biochim Biophys Acta Gen Subj. 2022 Feb 5;1866(5):130099. doi:, 10.1016/j.bbagen.2022.130099. PMID:35134491 doi:https://dx.doi.org/10.1016/j.bbagen.2022.130099

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OCA

[1] Kleiman FE, Manley JL. Functional interaction of BRCA1-associated BARD1 with polyadenylation factor CstF-50. Science. 1999 Sep 3;285(5433):1576-9. PMID:10477523

[2] Wu-Baer F, Lagrazon K, Yuan W, Baer R. The BRCA1/BARD1 heterodimer assembles polyubiquitin chains through an unconventional linkage involving lysine residue K6 of ubiquitin. J Biol Chem. 2003 Sep 12;278(37):34743-6. Epub 2003 Jul 30. PMID:12890688 doi:10.1074/jbc.C300249200

[3] Morris JR, Solomon E. BRCA1 : BARD1 induces the formation of conjugated ubiquitin structures, dependent on K6 of ubiquitin, in cells during DNA replication and repair. Hum Mol Genet. 2004 Apr 15;13(8):807-17. Epub 2004 Feb 19. PMID:14976165 doi:10.1093/hmg/ddh095

[4] Wu-Baer F, Ludwig T, Baer R. The UBXN1 protein associates with autoubiquitinated forms of the BRCA1 tumor suppressor and inhibits its enzymatic function. Mol Cell Biol. 2010 Jun;30(11):2787-98. doi: 10.1128/MCB.01056-09. Epub 2010 Mar , 29. PMID:20351172 doi:10.1128/MCB.01056-09

[5] Chen T, Yeh HW, Chen PP, Huang WT, Wu CY, Liao TC, Lin SL, Chen YY, Lin KT, Hsu SD, Cheng HC. BARD1 is an ATPase activating protein for OLA1. Biochim Biophys Acta Gen Subj. 2022 Feb 5;1866(5):130099. doi:, 10.1016/j.bbagen.2022.130099. PMID:35134491 doi:https://dx.doi.org/10.1016/j.bbagen.2022.130099

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[2]

[3]

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[5]

@@ Line 3: / Line 3: @@
 <StructureSection load='6m14' size='340' side='right'caption='[[6m14]], [[Resolution|resolution]] 1.88&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6m14]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6M14 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6M14 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6m14]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6M14 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6M14 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.8800184&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BARD1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/RING-type_E3_ubiquitin_transferase RING-type E3 ubiquitin transferase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.2.27 2.3.2.27] </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=6m14 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6m14 OCA], [https://pdbe.org/6m14 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6m14 RCSB], [https://www.ebi.ac.uk/pdbsum/6m14 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6m14 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/BARD1_HUMAN BARD1_HUMAN]] Probable E3 ubiquitin-protein ligase. The BRCA1-BARD1 heterodimer specifically mediates the formation of 'Lys-6'-linked polyubiquitin chains and coordinates a diverse range of cellular pathways such as DNA damage repair, ubiquitination and transcriptional regulation to maintain genomic stability. Plays a central role in the control of the cell cycle in response to DNA damage. Acts by mediating ubiquitin E3 ligase activity that is required for its tumor suppressor function. Also forms a heterodimer with CSTF1/CSTF-50 to modulate mRNA processing and RNAP II stability by inhibiting pre-mRNA 3' cleavage.<ref>PMID:10477523</ref> <ref>PMID:12890688</ref> <ref>PMID:14976165</ref> <ref>PMID:20351172</ref>
+[https://www.uniprot.org/uniprot/BARD1_HUMAN BARD1_HUMAN] Probable E3 ubiquitin-protein ligase. The BRCA1-BARD1 heterodimer specifically mediates the formation of 'Lys-6'-linked polyubiquitin chains and coordinates a diverse range of cellular pathways such as DNA damage repair, ubiquitination and transcriptional regulation to maintain genomic stability. Plays a central role in the control of the cell cycle in response to DNA damage. Acts by mediating ubiquitin E3 ligase activity that is required for its tumor suppressor function. Also forms a heterodimer with CSTF1/CSTF-50 to modulate mRNA processing and RNAP II stability by inhibiting pre-mRNA 3' cleavage.<ref>PMID:10477523</ref> <ref>PMID:12890688</ref> <ref>PMID:14976165</ref> <ref>PMID:20351172</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 24: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: RING-type E3 ubiquitin transferase]]
+[[Category: Chen T]]
-[[Category: Chen, T]]
+[[Category: Huang WT]]
-[[Category: Huang, W T]]
-[[Category: Antitumor protein]]
-[[Category: Brct]]
-[[Category: Disease mutation]]
-[[Category: Ola1]]
-[[Category: Transferase]]

6m14: Difference between revisions

Latest revision as of 15:10, 29 November 2023

Crystal Structure of the BARD1 BRCT Mutant

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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