5ons

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of the minimal DENR-MCTS1 complex

Structural highlights

5ons 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 2.14Å
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 succession of molecular events leading to eukaryotic translation reinitiation-whereby ribosomes terminate translation of a short open reading frame (ORF), resume scanning, and then translate a second ORF on the same mRNA-is not well understood. Density-regulated reinitiation and release factor (DENR) and multiple copies in T-cell lymphoma-1 (MCTS1) are implicated in promoting translation reinitiation both in vitro in translation extracts and in vivo. We present here the crystal structure of MCTS1 bound to a fragment of DENR. Based on this structure, we identify and experimentally validate that DENR residues Glu42, Tyr43, and Tyr46 are important for MCTS1 binding and that MCTS1 residue Phe104 is important for tRNA binding. Mutation of these residues reveals that DENR-MCTS1 dimerization and tRNA binding are both necessary for DENR and MCTS1 to promote translation reinitiation in human cells. These findings thereby link individual residues of DENR and MCTS1 to specific molecular functions of the complex. Since DENR-MCTS1 can bind tRNA in the absence of the ribosome, this suggests the DENR-MCTS1 complex could recruit tRNA to the ribosome during reinitiation analogously to the eukaryotic initiation factor 2 (eIF2) complex in cap-dependent translation.

DENR-MCTS1 heterodimerization and tRNA recruitment are required for translation reinitiation.,Ahmed YL, Schleich S, Bohlen J, Mandel N, Simon B, Sinning I, Teleman AA PLoS Biol. 2018 Jun 11;16(6):e2005160. doi: 10.1371/journal.pbio.2005160. PMID:29889857^[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
↑ Ahmed YL, Schleich S, Bohlen J, Mandel N, Simon B, Sinning I, Teleman AA. DENR-MCTS1 heterodimerization and tRNA recruitment are required for translation reinitiation. PLoS Biol. 2018 Jun 11;16(6):e2005160. doi: 10.1371/journal.pbio.2005160. PMID:29889857 doi:http://dx.doi.org/10.1371/journal.pbio.2005160

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/5ons"

Categories: Homo sapiens | Large Structures | Ahmed YL | Sinning I

@@ Line 1: / Line 1: @@
 ==Crystal structure of the minimal DENR-MCTS1 complex==
-<StructureSection load='5ons' size='340' side='right' caption='[[5ons]], [[Resolution|resolution]] 2.14&Aring;' scene=''>
+<StructureSection load='5ons' size='340' side='right'caption='[[5ons]], [[Resolution|resolution]] 2.14&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5ons]] 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=5ONS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ONS FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5ons]] 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=5ONS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ONS 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=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]] 2.14&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5vyc|5vyc]]</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=ZN:ZINC+ION'>ZN</scene></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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5ons FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ons OCA], [https://pdbe.org/5ons PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ons RCSB], [https://www.ebi.ac.uk/pdbsum/5ons PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ons ProSAT]</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=5ons FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ons OCA], [http://pdbe.org/5ons PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ons RCSB], [http://www.ebi.ac.uk/pdbsum/5ons PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ons 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 24: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
-[[Category: Ahmed, Y L]]
+[[Category: Large Structures]]
-[[Category: Sinning, I]]
+[[Category: Ahmed YL]]
-[[Category: Ribosome]]
+[[Category: Sinning I]]
-[[Category: Translation]]
-[[Category: Translation initiation]]

5ons

From Proteopedia

Current revision

Crystal structure of the minimal DENR-MCTS1 complex

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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