6k07

From Proteopedia

(Difference between revisions)

Revision as of 10:48, 18 December 2019

Crystal structure of REV7(R124A) in complex with a Shieldin3 fragment

Structural highlights

6k07 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	MAD2L2, MAD2B, REV7 (HUMAN), SHLD3, FLJ26957, RINN1 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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] [SHLD3_HUMAN] Component of the shieldin complex, which plays an important role in repair of DNA double-stranded breaks (DSBs). During G1 and S phase of the cell cycle, the complex functions downstream of TP53BP1 to promote non-homologous end joining (NHEJ) and suppress DNA end resection. Mediates various NHEJ-dependent processes including immunoglobulin class-switch recombination, and fusion of unprotected telomeres.^[6]

Publication Abstract from PubMed

Shieldin complex subunit 3 (SHLD3) is the apical subunit of a recently identified shieldin complex and plays a critical role in DNA double-strand break (DSB) repair. To fulfill its function in DNA repair, SHLD3 interacts with the mitotic spindle assembly checkpoint protein REV7 homolog (REV7), but the details of this interaction remain obscure. Here, we present the crystal structures of REV7 in complex with SHLD3's REV7-binding domain (RBD) at 2.2-2.3 A resolutions. The structures revealed that the ladle-shaped RBD in SHLD3 uses its N-terminal loop and C-terminal alpha-helix (alphaC-helix) in its interaction with REV7. The N-terminal loop exhibited a structure similar to those previously identified in other REV7-binding proteins, whereas the less conserved alphaC-helix region adopted a distinct mode for binding REV7. In vitro and in vivo binding analyses revealed that the N-terminal loop and alphaC-helix are both indispensable for high-affinity REV7 binding (with low-nanomolar affinity), underscoring the crucial role of SHLD3 alphaC-helix in protein binding. Moreover, binding kinetics analyses revealed that the REV7 "safety-belt" region, which plays a role in binding other proteins, is essential for SHLD3-REV7 binding, as this region retards the dissociation of the RBD from the bound REV7. Together, the findings of our study reveal the molecular basis of the SHLD3-REV7 interaction and provide critical insights into how SHLD3 recognizes REV7.

Structural basis for shieldin complex subunit 3-mediated recruitment of the checkpoint protein REV7 during DNA double-strand break repair.,Dai Y, Zhang F, Wang L, Shan S, Gong Z, Zhou Z J Biol Chem. 2019 Dec 3. pii: RA119.011464. doi: 10.1074/jbc.RA119.011464. PMID:31796627^[7]

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

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
↑ Gupta R, Somyajit K, Narita T, Maskey E, Stanlie A, Kremer M, Typas D, Lammers M, Mailand N, Nussenzweig A, Lukas J, Choudhary C. DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity. Cell. 2018 May 3;173(4):972-988.e23. doi: 10.1016/j.cell.2018.03.050. Epub 2018, Apr 12. PMID:29656893 doi:http://dx.doi.org/10.1016/j.cell.2018.03.050
↑ Dai Y, Zhang F, Wang L, Shan S, Gong Z, Zhou Z. Structural basis for shieldin complex subunit 3-mediated recruitment of the checkpoint protein REV7 during DNA double-strand break repair. J Biol Chem. 2019 Dec 3. pii: RA119.011464. doi: 10.1074/jbc.RA119.011464. PMID:31796627 doi:http://dx.doi.org/10.1074/jbc.RA119.011464

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6k07"

@@ Line 3: / Line 3: @@
 <StructureSection load='6k07' size='340' side='right'caption='[[6k07]], [[Resolution|resolution]] 2.24&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6k07]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6K07 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6K07 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6k07]] 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=6K07 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6K07 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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]), SHLD3, FLJ26957, RINN1 ([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=6k07 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6k07 OCA], [http://pdbe.org/6k07 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6k07 RCSB], [http://www.ebi.ac.uk/pdbsum/6k07 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6k07 ProSAT]</span></td></tr>
 </table>
 == 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/SHLD3_HUMAN SHLD3_HUMAN]] Component of the shieldin complex, which plays an important role in repair of DNA double-stranded breaks (DSBs). During G1 and S phase of the cell cycle, the complex functions downstream of TP53BP1 to promote non-homologous end joining (NHEJ) and suppress DNA end resection. Mediates various NHEJ-dependent processes including immunoglobulin class-switch recombination, and fusion of unprotected telomeres.<ref>PMID:29656893</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Shieldin complex subunit 3 (SHLD3) is the apical subunit of a recently identified shieldin complex and plays a critical role in DNA double-strand break (DSB) repair. To fulfill its function in DNA repair, SHLD3 interacts with the mitotic spindle assembly checkpoint protein REV7 homolog (REV7), but the details of this interaction remain obscure. Here, we present the crystal structures of REV7 in complex with SHLD3's REV7-binding domain (RBD) at 2.2-2.3 A resolutions. The structures revealed that the ladle-shaped RBD in SHLD3 uses its N-terminal loop and C-terminal alpha-helix (alphaC-helix) in its interaction with REV7. The N-terminal loop exhibited a structure similar to those previously identified in other REV7-binding proteins, whereas the less conserved alphaC-helix region adopted a distinct mode for binding REV7. In vitro and in vivo binding analyses revealed that the N-terminal loop and alphaC-helix are both indispensable for high-affinity REV7 binding (with low-nanomolar affinity), underscoring the crucial role of SHLD3 alphaC-helix in protein binding. Moreover, binding kinetics analyses revealed that the REV7 "safety-belt" region, which plays a role in binding other proteins, is essential for SHLD3-REV7 binding, as this region retards the dissociation of the RBD from the bound REV7. Together, the findings of our study reveal the molecular basis of the SHLD3-REV7 interaction and provide critical insights into how SHLD3 recognizes REV7.
+Structural basis for shieldin complex subunit 3-mediated recruitment of the checkpoint protein REV7 during DNA double-strand break repair.,Dai Y, Zhang F, Wang L, Shan S, Gong Z, Zhou Z J Biol Chem. 2019 Dec 3. pii: RA119.011464. doi: 10.1074/jbc.RA119.011464. PMID:31796627<ref>PMID:31796627</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 6k07" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Large Structures]]
 [[Category: Dai, Y]]

6k07

From Proteopedia

Revision as of 10:48, 18 December 2019

Crystal structure of REV7(R124A) in complex with a Shieldin3 fragment

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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