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| | ==Crystal structure of Rev7-K44A/R124A/A135D in complex with Rev3-RBM2 (residues 1988-2014)== | | ==Crystal structure of Rev7-K44A/R124A/A135D in complex with Rev3-RBM2 (residues 1988-2014)== |
| - | <StructureSection load='6bcd' size='340' side='right' caption='[[6bcd]], [[Resolution|resolution]] 1.43Å' scene=''> | + | <StructureSection load='6bcd' size='340' side='right'caption='[[6bcd]], [[Resolution|resolution]] 1.43Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6bcd]] is a 2 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=6BCD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BCD FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6bcd]] 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=6BCD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6BCD FirstGlance]. <br> |
| - | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6bc8|6bc8]]</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]] 1.43Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MAD2L2, MAD2B, REV7 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), REV3L, POLZ, REV3 ([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'>[https://proteopedia.org/fgij/fg.htm?mol=6bcd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bcd OCA], [https://pdbe.org/6bcd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6bcd RCSB], [https://www.ebi.ac.uk/pdbsum/6bcd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6bcd ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/DNA-directed_DNA_polymerase DNA-directed DNA polymerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.7 2.7.7.7] </span></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=6bcd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bcd OCA], [http://pdbe.org/6bcd PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6bcd RCSB], [http://www.ebi.ac.uk/pdbsum/6bcd PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6bcd ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/MD2L2_HUMAN MD2L2_HUMAN]] Adapter protein able to interact with different proteins and involved in different biological processes. Mediates the interaction between the error-prone DNA polymerase zeta catalytic subunit REV3L and the inserter polymerase REV1, thereby mediating the second polymerase switching in translesion DNA synthesis. Translesion DNA synthesis releases the replication blockade of replicative polymerases, stalled in presence of DNA lesions. May also regulate another aspect of cellular response to DNA damage through regulation of the JNK-mediated phosphorylation and activation of the transcriptional activator ELK1. Inhibits the FZR1- and probably CDC20-mediated activation of the anaphase promoting complex APC thereby regulating progression through the cell cycle. Regulates TCF7L2-mediated gene transcription and may play a role in epithelial-mesenchymal transdifferentiation.<ref>PMID:11459825</ref> <ref>PMID:11459826</ref> <ref>PMID:17719540</ref> <ref>PMID:17296730</ref> <ref>PMID:19443654</ref> [[http://www.uniprot.org/uniprot/REV3L_HUMAN REV3L_HUMAN]] Catalytic subunit of the DNA polymerase zeta complex, an error-prone polymerase specialized in translesion DNA synthesis (TLS). Lacks an intrinsic 3'-5' exonuclease activity and thus has no proofreading function.<ref>PMID:24449906</ref> | + | [https://www.uniprot.org/uniprot/MD2L2_HUMAN MD2L2_HUMAN] Adapter protein able to interact with different proteins and involved in different biological processes. Mediates the interaction between the error-prone DNA polymerase zeta catalytic subunit REV3L and the inserter polymerase REV1, thereby mediating the second polymerase switching in translesion DNA synthesis. Translesion DNA synthesis releases the replication blockade of replicative polymerases, stalled in presence of DNA lesions. May also regulate another aspect of cellular response to DNA damage through regulation of the JNK-mediated phosphorylation and activation of the transcriptional activator ELK1. Inhibits the FZR1- and probably CDC20-mediated activation of the anaphase promoting complex APC thereby regulating progression through the cell cycle. Regulates TCF7L2-mediated gene transcription and may play a role in epithelial-mesenchymal transdifferentiation.<ref>PMID:11459825</ref> <ref>PMID:11459826</ref> <ref>PMID:17719540</ref> <ref>PMID:17296730</ref> <ref>PMID:19443654</ref> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | The translesion synthesis (TLS) polymerases Polzeta and Rev1 form a complex that enables replication of damaged DNA. The Rev7 subunit of Polzeta, which is a multifaceted HORMA (Hop1, Rev7, Mad2) protein with roles in TLS, DNA repair, and cell-cycle control, facilitates assembly of this complex by binding Rev1 and the catalytic subunit of Polzeta, Rev3. Rev7 interacts with Rev3 by a mechanism conserved among HORMA proteins, whereby an open-to-closed transition locks the ligand underneath the "safety belt" loop. Dimerization of HORMA proteins promotes binding and release of this ligand, as exemplified by the Rev7 homolog, Mad2. Here, we investigate the dimerization of Rev7 when bound to the two Rev7-binding motifs (RBMs) in Rev3 by combining in vitro analyses of Rev7 structure and interactions with a functional assay in a Rev7(-/-) cell line. We demonstrate that Rev7 uses the conventional HORMA dimerization interface both to form a homodimer when tethered by the two RBMs in Rev3 and to heterodimerize with other HORMA domains, Mad2 and p31(comet) Structurally, the Rev7 dimer can bind only one copy of Rev1, revealing an unexpected Rev1/Polzeta architecture. In cells, mutation of the Rev7 dimer interface increases sensitivity to DNA damage. These results provide insights into the structure of the Rev1/Polzeta TLS assembly and highlight the function of Rev7 homo- and heterodimerization. |
| | + | |
| | + | Rev7 dimerization is important for assembly and function of the Rev1/Polzeta translesion synthesis complex.,Rizzo AA, Vassel FM, Chatterjee N, D'Souza S, Li Y, Hao B, Hemann MT, Walker GC, Korzhnev DM Proc Natl Acad Sci U S A. 2018 Aug 15. pii: 1801149115. doi:, 10.1073/pnas.1801149115. PMID:30111544<ref>PMID:30111544</ref> |
| | + | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 6bcd" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[DNA polymerase 3D structures|DNA polymerase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: DNA-directed DNA polymerase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Large Structures]] |
| - | [[Category: Hao, B]] | + | [[Category: Hao B]] |
| - | [[Category: Korzhnev, D M]] | + | [[Category: Korzhnev DM]] |
| - | [[Category: Li, Y]] | + | [[Category: Li Y]] |
| - | [[Category: Rizzo, A A]] | + | [[Category: Rizzo AA]] |
| - | [[Category: Dna damage tolerance]]
| + | |
| - | [[Category: Replication]]
| + | |
| - | [[Category: Translesion dna synthesis]]
| + | |
| Structural highlights
Function
MD2L2_HUMAN Adapter protein able to interact with different proteins and involved in different biological processes. Mediates the interaction between the error-prone DNA polymerase zeta catalytic subunit REV3L and the inserter polymerase REV1, thereby mediating the second polymerase switching in translesion DNA synthesis. Translesion DNA synthesis releases the replication blockade of replicative polymerases, stalled in presence of DNA lesions. May also regulate another aspect of cellular response to DNA damage through regulation of the JNK-mediated phosphorylation and activation of the transcriptional activator ELK1. Inhibits the FZR1- and probably CDC20-mediated activation of the anaphase promoting complex APC thereby regulating progression through the cell cycle. Regulates TCF7L2-mediated gene transcription and may play a role in epithelial-mesenchymal transdifferentiation.[1] [2] [3] [4] [5]
Publication Abstract from PubMed
The translesion synthesis (TLS) polymerases Polzeta and Rev1 form a complex that enables replication of damaged DNA. The Rev7 subunit of Polzeta, which is a multifaceted HORMA (Hop1, Rev7, Mad2) protein with roles in TLS, DNA repair, and cell-cycle control, facilitates assembly of this complex by binding Rev1 and the catalytic subunit of Polzeta, Rev3. Rev7 interacts with Rev3 by a mechanism conserved among HORMA proteins, whereby an open-to-closed transition locks the ligand underneath the "safety belt" loop. Dimerization of HORMA proteins promotes binding and release of this ligand, as exemplified by the Rev7 homolog, Mad2. Here, we investigate the dimerization of Rev7 when bound to the two Rev7-binding motifs (RBMs) in Rev3 by combining in vitro analyses of Rev7 structure and interactions with a functional assay in a Rev7(-/-) cell line. We demonstrate that Rev7 uses the conventional HORMA dimerization interface both to form a homodimer when tethered by the two RBMs in Rev3 and to heterodimerize with other HORMA domains, Mad2 and p31(comet) Structurally, the Rev7 dimer can bind only one copy of Rev1, revealing an unexpected Rev1/Polzeta architecture. In cells, mutation of the Rev7 dimer interface increases sensitivity to DNA damage. These results provide insights into the structure of the Rev1/Polzeta TLS assembly and highlight the function of Rev7 homo- and heterodimerization.
Rev7 dimerization is important for assembly and function of the Rev1/Polzeta translesion synthesis complex.,Rizzo AA, Vassel FM, Chatterjee N, D'Souza S, Li Y, Hao B, Hemann MT, Walker GC, Korzhnev DM Proc Natl Acad Sci U S A. 2018 Aug 15. pii: 1801149115. doi:, 10.1073/pnas.1801149115. PMID:30111544[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Pfleger CM, Salic A, Lee E, Kirschner MW. Inhibition of Cdh1-APC by the MAD2-related protein MAD2L2: a novel mechanism for regulating Cdh1. Genes Dev. 2001 Jul 15;15(14):1759-64. PMID:11459825 doi:10.1101/gad.897901
- ↑ Chen J, Fang G. MAD2B is an inhibitor of the anaphase-promoting complex. Genes Dev. 2001 Jul 15;15(14):1765-70. PMID:11459826 doi:10.1101/gad.898701
- ↑ Iwai H, Kim M, Yoshikawa Y, Ashida H, Ogawa M, Fujita Y, Muller D, Kirikae T, Jackson PK, Kotani S, Sasakawa C. A bacterial effector targets Mad2L2, an APC inhibitor, to modulate host cell cycling. Cell. 2007 Aug 24;130(4):611-23. PMID:17719540 doi:10.1016/j.cell.2007.06.043
- ↑ Zhang L, Yang SH, Sharrocks AD. Rev7/MAD2B links c-Jun N-terminal protein kinase pathway signaling to activation of the transcription factor Elk-1. Mol Cell Biol. 2007 Apr;27(8):2861-9. Epub 2007 Feb 12. PMID:17296730 doi:10.1128/MCB.02276-06
- ↑ Hong CF, Chou YT, Lin YS, Wu CW. MAD2B, a novel TCF4-binding protein, modulates TCF4-mediated epithelial-mesenchymal transdifferentiation. J Biol Chem. 2009 Jul 17;284(29):19613-22. doi: 10.1074/jbc.M109.005017. Epub, 2009 May 14. PMID:19443654 doi:10.1074/jbc.M109.005017
- ↑ Rizzo AA, Vassel FM, Chatterjee N, D'Souza S, Li Y, Hao B, Hemann MT, Walker GC, Korzhnev DM. Rev7 dimerization is important for assembly and function of the Rev1/Polzeta translesion synthesis complex. Proc Natl Acad Sci U S A. 2018 Aug 15. pii: 1801149115. doi:, 10.1073/pnas.1801149115. PMID:30111544 doi:http://dx.doi.org/10.1073/pnas.1801149115
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