2wvr: Difference between revisions

Latest revision as of 10:18, 9 May 2024

Human Cdt1:Geminin complex

Structural highlights

2wvr is a 3 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 3.3Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

GEMI_HUMAN Inhibits DNA replication by preventing the incorporation of MCM complex into pre-replication complex (pre-RC). It is degraded during the mitotic phase of the cell cycle. Its destruction at the metaphase-anaphase transition permits replication in the succeeding cell cycle.^[1] ^[2] ^[3] Inhibits the transcriptional activity of a subset of Hox proteins, enrolling them in cell proliferative control.^[4] ^[5] ^[6]

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

All organisms need to ensure that no DNA segments are rereplicated in a single cell cycle. Eukaryotes achieve this through a process called origin licensing, which involves tight spatiotemporal control of the assembly of prereplicative complexes (pre-RCs) onto chromatin. Cdt1 is a key component and crucial regulator of pre-RC assembly. In higher eukaryotes, timely inhibition of Cdt1 by Geminin is essential to prevent DNA rereplication. Here, we address the mechanism of DNA licensing inhibition by Geminin, by combining X-ray crystallography, small-angle X-ray scattering, and functional studies in Xenopus and mammalian cells. Our findings show that the Cdt1:Geminin complex can exist in two distinct forms, a "permissive" heterotrimer and an "inhibitory" heterohexamer. Specific Cdt1 residues, buried in the heterohexamer, are important for licensing. We postulate that the transition between the heterotrimer and the heterohexamer represents a molecular switch between licensing-competent and licensing-defective states.

Quaternary structure of the human Cdt1-Geminin complex regulates DNA replication licensing.,De Marco V, Gillespie PJ, Li A, Karantzelis N, Christodoulou E, Klompmaker R, van Gerwen S, Fish A, Petoukhov MV, Iliou MS, Lygerou Z, Medema RH, Blow JJ, Svergun DI, Taraviras S, Perrakis A Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):19807-12. Epub 2009 Nov 11. PMID:19906994^[7]

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

References

↑ McGarry TJ, Kirschner MW. Geminin, an inhibitor of DNA replication, is degraded during mitosis. Cell. 1998 Jun 12;93(6):1043-53. PMID:9635433
↑ Sugimoto N, Tatsumi Y, Tsurumi T, Matsukage A, Kiyono T, Nishitani H, Fujita M. Cdt1 phosphorylation by cyclin A-dependent kinases negatively regulates its function without affecting geminin binding. J Biol Chem. 2004 May 7;279(19):19691-7. Epub 2004 Mar 1. PMID:14993212 doi:10.1074/jbc.M313175200
↑ Zhou B, Liu C, Xu Z, Zhu G. Structural basis for homeodomain recognition by the cell-cycle regulator Geminin. Proc Natl Acad Sci U S A. 2012 May 21. PMID:22615398 doi:10.1073/pnas.1200874109
↑ McGarry TJ, Kirschner MW. Geminin, an inhibitor of DNA replication, is degraded during mitosis. Cell. 1998 Jun 12;93(6):1043-53. PMID:9635433
↑ Sugimoto N, Tatsumi Y, Tsurumi T, Matsukage A, Kiyono T, Nishitani H, Fujita M. Cdt1 phosphorylation by cyclin A-dependent kinases negatively regulates its function without affecting geminin binding. J Biol Chem. 2004 May 7;279(19):19691-7. Epub 2004 Mar 1. PMID:14993212 doi:10.1074/jbc.M313175200
↑ Zhou B, Liu C, Xu Z, Zhu G. Structural basis for homeodomain recognition by the cell-cycle regulator Geminin. Proc Natl Acad Sci U S A. 2012 May 21. PMID:22615398 doi:10.1073/pnas.1200874109
↑ De Marco V, Gillespie PJ, Li A, Karantzelis N, Christodoulou E, Klompmaker R, van Gerwen S, Fish A, Petoukhov MV, Iliou MS, Lygerou Z, Medema RH, Blow JJ, Svergun DI, Taraviras S, Perrakis A. Quaternary structure of the human Cdt1-Geminin complex regulates DNA replication licensing. Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):19807-12. Epub 2009 Nov 11. PMID:19906994 doi:10.1073/pnas.0905281106

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] McGarry TJ, Kirschner MW. Geminin, an inhibitor of DNA replication, is degraded during mitosis. Cell. 1998 Jun 12;93(6):1043-53. PMID:9635433

[2] Sugimoto N, Tatsumi Y, Tsurumi T, Matsukage A, Kiyono T, Nishitani H, Fujita M. Cdt1 phosphorylation by cyclin A-dependent kinases negatively regulates its function without affecting geminin binding. J Biol Chem. 2004 May 7;279(19):19691-7. Epub 2004 Mar 1. PMID:14993212 doi:10.1074/jbc.M313175200

[3] Zhou B, Liu C, Xu Z, Zhu G. Structural basis for homeodomain recognition by the cell-cycle regulator Geminin. Proc Natl Acad Sci U S A. 2012 May 21. PMID:22615398 doi:10.1073/pnas.1200874109

[4] McGarry TJ, Kirschner MW. Geminin, an inhibitor of DNA replication, is degraded during mitosis. Cell. 1998 Jun 12;93(6):1043-53. PMID:9635433

[5] Sugimoto N, Tatsumi Y, Tsurumi T, Matsukage A, Kiyono T, Nishitani H, Fujita M. Cdt1 phosphorylation by cyclin A-dependent kinases negatively regulates its function without affecting geminin binding. J Biol Chem. 2004 May 7;279(19):19691-7. Epub 2004 Mar 1. PMID:14993212 doi:10.1074/jbc.M313175200

[6] Zhou B, Liu C, Xu Z, Zhu G. Structural basis for homeodomain recognition by the cell-cycle regulator Geminin. Proc Natl Acad Sci U S A. 2012 May 21. PMID:22615398 doi:10.1073/pnas.1200874109

[7] De Marco V, Gillespie PJ, Li A, Karantzelis N, Christodoulou E, Klompmaker R, van Gerwen S, Fish A, Petoukhov MV, Iliou MS, Lygerou Z, Medema RH, Blow JJ, Svergun DI, Taraviras S, Perrakis A. Quaternary structure of the human Cdt1-Geminin complex regulates DNA replication licensing. Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):19807-12. Epub 2009 Nov 11. PMID:19906994 doi:10.1073/pnas.0905281106

[1]

[2]

[3]

[4]

[5]

[6]

[7]

@@ Line 3: / Line 3: @@
 <StructureSection load='2wvr' size='340' side='right'caption='[[2wvr]], [[Resolution|resolution]] 3.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2wvr]] is a 3 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=2WVR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2WVR FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2wvr]] is a 3 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=2WVR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2WVR FirstGlance]. <br>
-</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1uii|1uii]], [[1t6f|1t6f]]</div></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]] 3.3&#8491;</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=2wvr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wvr OCA], [https://pdbe.org/2wvr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2wvr RCSB], [https://www.ebi.ac.uk/pdbsum/2wvr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2wvr ProSAT]</span></td></tr>
 </table>
-== Disease ==
-[[https://www.uniprot.org/uniprot/CDT1_HUMAN CDT1_HUMAN]] Defects in CDT1 are the cause of Meier-Gorlin syndrome type 4 (MGORS4) [MIM:[https://omim.org/entry/613804 613804]]. MGORS4 is a syndrome characterized by bilateral microtia, aplasia/hypoplasia of the patellae, and severe intrauterine and postnatal growth retardation with short stature and poor weight gain. Additional clinical findings include anomalies of cranial sutures, microcephaly, apparently low-set and simple ears, microstomia, full lips, highly arched or cleft palate, micrognathia, genitourinary tract anomalies, and various skeletal anomalies. While almost all cases have primordial dwarfism with substantial prenatal and postnatal growth retardation, not all cases have microcephaly, and microtia and absent/hypoplastic patella are absent in some. Despite the presence of microcephaly, intellect is usually normal.<ref>PMID:21358632</ref> <ref>PMID:21358631</ref>
 == Function ==
-[[https://www.uniprot.org/uniprot/GEMI_HUMAN GEMI_HUMAN]] Inhibits DNA replication by preventing the incorporation of MCM complex into pre-replication complex (pre-RC). It is degraded during the mitotic phase of the cell cycle. Its destruction at the metaphase-anaphase transition permits replication in the succeeding cell cycle.<ref>PMID:9635433</ref> <ref>PMID:14993212</ref> <ref>PMID:22615398</ref>   Inhibits the transcriptional activity of a subset of Hox proteins, enrolling them in cell proliferative control.<ref>PMID:9635433</ref> <ref>PMID:14993212</ref> <ref>PMID:22615398</ref>  [[https://www.uniprot.org/uniprot/CDT1_HUMAN CDT1_HUMAN]] Cooperates with CDC6 to promote the loading of the mini-chromosome maintenance complex onto chromatin to form the pre-replication complex necessary to initiate DNA replication. Binds DNA in a sequence-, strand-, and conformation-independent manner. Potential oncogene.<ref>PMID:11125146</ref> <ref>PMID:21856198</ref> <ref>PMID:14672932</ref> <ref>PMID:14993212</ref> [UniProtKB:Q8R4E9]
+[https://www.uniprot.org/uniprot/GEMI_HUMAN GEMI_HUMAN] Inhibits DNA replication by preventing the incorporation of MCM complex into pre-replication complex (pre-RC). It is degraded during the mitotic phase of the cell cycle. Its destruction at the metaphase-anaphase transition permits replication in the succeeding cell cycle.<ref>PMID:9635433</ref> <ref>PMID:14993212</ref> <ref>PMID:22615398</ref>   Inhibits the transcriptional activity of a subset of Hox proteins, enrolling them in cell proliferative control.<ref>PMID:9635433</ref> <ref>PMID:14993212</ref> <ref>PMID:22615398</ref>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 34: / Line 32: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Marco, V De]]
+[[Category: De Marco V]]
-[[Category: Perrakis, A]]
+[[Category: Perrakis A]]
-[[Category: Acetylation]]
-[[Category: Cell cycle]]
-[[Category: Coiled coil]]
-[[Category: Dna replication]]
-[[Category: Dna replication inhibitor]]
-[[Category: Dna replication license]]
-[[Category: Dna-binding]]
-[[Category: Nucleus]]
-[[Category: Phosphoprotein]]
-[[Category: Polymorphism]]
-[[Category: Proto-oncogene]]
-[[Category: Replication]]
-[[Category: Ubl conjugation]]

2wvr: Difference between revisions

Latest revision as of 10:18, 9 May 2024

Human Cdt1:Geminin complex

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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