6ms4

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of the DENR-MCT-1 complex

Structural highlights

6ms4 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 2.001Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MCTS1_HUMAN Anti-oncogene that play a role in cell cycle regulation; decreases cell doubling time and anchorage-dependent growth; shortens the duration of G1 transit time and G1/S transition. When constituvely expressed, increases CDK4 and CDK6 kinases activity and CCND1/cyclin D1 protein level, as well as G1 cyclin/CDK complex formation. Plays a role as translation enhancer; Recruits the density-regulated protein/DENR and binds to the cap complex of the 5'-terminus of mRNAs, subsequently altering the mRNA translation profile; Up-regulates protein levels of BCL2L2, TFDP1, MRE11A, CCND1 and E2F1, while mRNA levels remains constant. Hyperactivates DNA damage signaling pathway; increased gamma-irradiation-induced phosphorylation of histone H2AX, and induces damage foci formation. Increases the overall number of chromosomal abnormalities such as larger chromosomes formation and multiples chromosomal fusions when overexpressed in gamma-irradiated cells. May play a role in promoting lymphoid tumor development: lymphoid cell lines overexpressing MCTS1 exhibit increased growth rates and display increased protection against apoptosis. May contribute to the pathogenesis and progression of breast cancer via promotion of angiogenesis through the decline of inhibitory THBS1/thrombospondin-1, and inhibition of apoptosis. Involved in the process of proteasome degradation to down-regulate Tumor suppressor p53/TP53 in breast cancer cell; Positively regulates phosphorylation of MAPK1 and MAPK3.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9]

Publication Abstract from PubMed

The density-regulated protein (DENR) and the malignant T cell-amplified sequence 1 (MCT-1/MCTS1) oncoprotein support noncanonical translation initiation, promote translation reinitiation on a specific set of mRNAs with short upstream reading frames, and regulate ribosome recycling. DENR and MCT-1 form a heterodimer, which binds to the ribosome. We determined the crystal structure of the heterodimer formed by human MCT-1 and the N-terminal domain of DENR at 2.0-A resolution. The structure of the heterodimer reveals atomic details of the mechanism of DENR and MCT-1 interaction. Four conserved cysteine residues of DENR (C34, C37, C44, C53) form a classical tetrahedral zinc ion-binding site, which preserves the structure of the DENR's MCT-1-binding interface that is essential for the dimerization. Substitution of all four cysteines by alanine abolished a heterodimer formation. Our findings elucidate further the mechanism of regulation of DENR-MCT-1 activities in unconventional translation initiation, reinitiation, and recycling.

Crystal structure of the DENR-MCT-1 complex revealed zinc-binding site essential for heterodimer formation.,Lomakin IB, Dmitriev SE, Steitz TA Proc Natl Acad Sci U S A. 2018 Dec 24. pii: 1809688116. doi:, 10.1073/pnas.1809688116. PMID:30584092^[10]

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

References

↑ Prosniak M, Dierov J, Okami K, Tilton B, Jameson B, Sawaya BE, Gartenhaus RB. A novel candidate oncogene, MCT-1, is involved in cell cycle progression. Cancer Res. 1998 Oct 1;58(19):4233-7. PMID:9766643
↑ Dierov J, Prosniak M, Gallia G, Gartenhaus RB. Increased G1 cyclin/cdk activity in cells overexpressing the candidate oncogene, MCT-1. J Cell Biochem. 1999 Sep 15;74(4):544-50. PMID:10440924
↑ Herbert GB, Shi B, Gartenhaus RB. Expression and stabilization of the MCT-1 protein by DNA damaging agents. Oncogene. 2001 Oct 11;20(46):6777-83. PMID:11709712 doi:10.1038/sj.onc.1204881
↑ Shi B, Hsu HL, Evens AM, Gordon LI, Gartenhaus RB. Expression of the candidate MCT-1 oncogene in B- and T-cell lymphoid malignancies. Blood. 2003 Jul 1;102(1):297-302. Epub 2003 Mar 13. PMID:12637315 doi:10.1182/blood-2002-11-3486
↑ Levenson AS, Thurn KE, Simons LA, Veliceasa D, Jarrett J, Osipo C, Jordan VC, Volpert OV, Satcher RL Jr, Gartenhaus RB. MCT-1 oncogene contributes to increased in vivo tumorigenicity of MCF7 cells by promotion of angiogenesis and inhibition of apoptosis. Cancer Res. 2005 Dec 1;65(23):10651-6. PMID:16322206 doi:10.1158/0008-5472.CAN-05-0845
↑ Hsu HL, Shi B, Gartenhaus RB. The MCT-1 oncogene product impairs cell cycle checkpoint control and transforms human mammary epithelial cells. Oncogene. 2005 Jul 21;24(31):4956-64. PMID:15897892 doi:10.1038/sj.onc.1208680
↑ Reinert LS, Shi B, Nandi S, Mazan-Mamczarz K, Vitolo M, Bachman KE, He H, Gartenhaus RB. MCT-1 protein interacts with the cap complex and modulates messenger RNA translational profiles. Cancer Res. 2006 Sep 15;66(18):8994-9001. PMID:16982740 doi:66/18/8994
↑ Hsu HL, Choy CO, Kasiappan R, Shih HJ, Sawyer JR, Shu CL, Chu KL, Chen YR, Hsu HF, Gartenhaus RB. MCT-1 oncogene downregulates p53 and destabilizes genome structure in the response to DNA double-strand damage. DNA Repair (Amst). 2007 Sep 1;6(9):1319-32. Epub 2007 Apr 6. PMID:17416211 doi:10.1016/j.dnarep.2007.02.028
↑ Nandi S, Reinert LS, Hachem A, Mazan-Mamczarz K, Hagner P, He H, Gartenhaus RB. Phosphorylation of MCT-1 by p44/42 MAPK is required for its stabilization in response to DNA damage. Oncogene. 2007 Apr 5;26(16):2283-9. Epub 2006 Oct 2. PMID:17016429 doi:10.1038/sj.onc.1210030
↑ Lomakin IB, Dmitriev SE, Steitz TA. Crystal structure of the DENR-MCT-1 complex revealed zinc-binding site essential for heterodimer formation. Proc Natl Acad Sci U S A. 2018 Dec 24. pii: 1809688116. doi:, 10.1073/pnas.1809688116. PMID:30584092 doi:http://dx.doi.org/10.1073/pnas.1809688116

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/6ms4"

Categories: Homo sapiens | Large Structures | Dmitriev SE | Lomakin IB | Steitz TA

@@ Line 3: / Line 3: @@
 <StructureSection load='6ms4' size='340' side='right'caption='[[6ms4]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6ms4]] 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=6MS4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MS4 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6ms4]] 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=6MS4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6MS4 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 2.001&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MCTS1, MCT1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), DENR, DRP1, H14 ([http://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=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=6ms4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ms4 OCA], [http://pdbe.org/6ms4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ms4 RCSB], [http://www.ebi.ac.uk/pdbsum/6ms4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ms4 ProSAT]</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=6ms4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ms4 OCA], [https://pdbe.org/6ms4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ms4 RCSB], [https://www.ebi.ac.uk/pdbsum/6ms4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ms4 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/MCTS1_HUMAN MCTS1_HUMAN]] Anti-oncogene that play a role in cell cycle regulation; decreases cell doubling time and anchorage-dependent growth; shortens the duration of G1 transit time and G1/S transition. When constituvely expressed, increases CDK4 and CDK6 kinases activity and CCND1/cyclin D1 protein level, as well as G1 cyclin/CDK complex formation. Plays a role as translation enhancer; Recruits the density-regulated protein/DENR and binds to the cap complex of the 5'-terminus of mRNAs, subsequently altering the mRNA translation profile; Up-regulates protein levels of BCL2L2, TFDP1, MRE11A, CCND1 and E2F1, while mRNA levels remains constant. Hyperactivates DNA damage signaling pathway; increased gamma-irradiation-induced phosphorylation of histone H2AX, and induces damage foci formation. Increases the overall number of chromosomal abnormalities such as larger chromosomes formation and multiples chromosomal fusions when overexpressed in gamma-irradiated cells. May play a role in promoting lymphoid tumor development: lymphoid cell lines overexpressing MCTS1 exhibit increased growth rates and display increased protection against apoptosis. May contribute to the pathogenesis and progression of breast cancer via promotion of angiogenesis through the decline of inhibitory THBS1/thrombospondin-1, and inhibition of apoptosis. Involved in the process of proteasome degradation to down-regulate Tumor suppressor p53/TP53 in breast cancer cell; Positively regulates phosphorylation of MAPK1 and MAPK3.<ref>PMID:9766643</ref> <ref>PMID:10440924</ref> <ref>PMID:11709712</ref> <ref>PMID:12637315</ref> <ref>PMID:16322206</ref> <ref>PMID:15897892</ref> <ref>PMID:16982740</ref> <ref>PMID:17416211</ref> <ref>PMID:17016429</ref>  [[http://www.uniprot.org/uniprot/DENR_HUMAN DENR_HUMAN]] May be involved in the translation of target mRNAs by scanning and recognition of the initiation codon. Involved in translation initiation; promotes recruitmnet of aminoacetyled initiator tRNA to P site of 40S ribosomes. Can promote release of deacylated tRNA and mRNA from recycled 40S subunits following ABCE1-mediated dissociation of post-termination ribosomal complexes into subunits. Plays a role in the modulation of the translational profile of a subset of cancer-related mRNAs when recruited to the translational initiation complex by the oncogene MCTS1.<ref>PMID:16982740</ref> <ref>PMID:17878526</ref> <ref>PMID:20713520</ref>
+[https://www.uniprot.org/uniprot/MCTS1_HUMAN MCTS1_HUMAN] Anti-oncogene that play a role in cell cycle regulation; decreases cell doubling time and anchorage-dependent growth; shortens the duration of G1 transit time and G1/S transition. When constituvely expressed, increases CDK4 and CDK6 kinases activity and CCND1/cyclin D1 protein level, as well as G1 cyclin/CDK complex formation. Plays a role as translation enhancer; Recruits the density-regulated protein/DENR and binds to the cap complex of the 5'-terminus of mRNAs, subsequently altering the mRNA translation profile; Up-regulates protein levels of BCL2L2, TFDP1, MRE11A, CCND1 and E2F1, while mRNA levels remains constant. Hyperactivates DNA damage signaling pathway; increased gamma-irradiation-induced phosphorylation of histone H2AX, and induces damage foci formation. Increases the overall number of chromosomal abnormalities such as larger chromosomes formation and multiples chromosomal fusions when overexpressed in gamma-irradiated cells. May play a role in promoting lymphoid tumor development: lymphoid cell lines overexpressing MCTS1 exhibit increased growth rates and display increased protection against apoptosis. May contribute to the pathogenesis and progression of breast cancer via promotion of angiogenesis through the decline of inhibitory THBS1/thrombospondin-1, and inhibition of apoptosis. Involved in the process of proteasome degradation to down-regulate Tumor suppressor p53/TP53 in breast cancer cell; Positively regulates phosphorylation of MAPK1 and MAPK3.<ref>PMID:9766643</ref> <ref>PMID:10440924</ref> <ref>PMID:11709712</ref> <ref>PMID:12637315</ref> <ref>PMID:16322206</ref> <ref>PMID:15897892</ref> <ref>PMID:16982740</ref> <ref>PMID:17416211</ref> <ref>PMID:17016429</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 23: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Dmitriev, S E]]
+[[Category: Dmitriev SE]]
-[[Category: Lomakin, I B]]
+[[Category: Lomakin IB]]
-[[Category: Steitz, T A]]
+[[Category: Steitz TA]]
-[[Category: Reinitiation]]
-[[Category: Ribosome]]
-[[Category: Translation]]
-[[Category: Trna binding]]
-[[Category: Zinc binding]]

6ms4

From Proteopedia

Current revision

Crystal structure of the DENR-MCT-1 complex

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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