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| | <StructureSection load='5vok' size='340' side='right'caption='[[5vok]], [[Resolution|resolution]] 2.89Å' scene=''> | | <StructureSection load='5vok' size='340' side='right'caption='[[5vok]], [[Resolution|resolution]] 2.89Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5vok]] is a 8 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=5VOK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5VOK FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5vok]] is a 8 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=5VOK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5VOK FirstGlance]. <br> |
| - | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">LAMTOR5, HBXIP, XIP ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), LAMTOR4, C7orf59 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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]] 2.89Å</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=5vok FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vok OCA], [http://pdbe.org/5vok PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5vok RCSB], [http://www.ebi.ac.uk/pdbsum/5vok PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5vok 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=5vok FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vok OCA], [https://pdbe.org/5vok PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5vok RCSB], [https://www.ebi.ac.uk/pdbsum/5vok PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5vok ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/LTOR5_HUMAN LTOR5_HUMAN]] As part of the Ragulator complex it is involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids. Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator functions as a guanine nucleotide exchange factor activating the small GTPases Rag. Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated. When complexed to BIRC5, interferes with apoptosome assembly, preventing recruitment of pro-caspase-9 to oligomerized APAF1, thereby selectively suppressing apoptosis initiated via the mitochondrial/cytochrome c pathway. Down-regulates hepatitis B virus (HBV) replication.<ref>PMID:12773388</ref> <ref>PMID:22980980</ref> [[http://www.uniprot.org/uniprot/LTOR4_HUMAN LTOR4_HUMAN]] As part of the Ragulator complex it is involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids. Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator functions as a guanine nucleotide exchange factor activating the small GTPases Rag. Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated.<ref>PMID:22980980</ref> | + | [https://www.uniprot.org/uniprot/LTOR5_HUMAN LTOR5_HUMAN] As part of the Ragulator complex it is involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids. Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator functions as a guanine nucleotide exchange factor activating the small GTPases Rag. Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated. When complexed to BIRC5, interferes with apoptosome assembly, preventing recruitment of pro-caspase-9 to oligomerized APAF1, thereby selectively suppressing apoptosis initiated via the mitochondrial/cytochrome c pathway. Down-regulates hepatitis B virus (HBV) replication.<ref>PMID:12773388</ref> <ref>PMID:22980980</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Aparicio, R]] | + | [[Category: Aparicio R]] |
| - | [[Category: Bar-Peled, L]] | + | [[Category: Bar-Peled L]] |
| - | [[Category: Nascimento, A F.Z]] | + | [[Category: Nascimento AFZ]] |
| - | [[Category: Rasheed, N]] | + | [[Category: Rasheed N]] |
| - | [[Category: Sabatini, D M]] | + | [[Category: Sabatini DM]] |
| - | [[Category: Shen, K]] | + | [[Category: Shen K]] |
| - | [[Category: Smetana, J H.C]] | + | [[Category: Smetana JHC]] |
| - | [[Category: C7orf59]]
| + | |
| - | [[Category: Mtor]]
| + | |
| - | [[Category: Ragulator]]
| + | |
| - | [[Category: Roadblock]]
| + | |
| - | [[Category: Signaling protein]]
| + | |
| Structural highlights
Function
LTOR5_HUMAN As part of the Ragulator complex it is involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids. Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator functions as a guanine nucleotide exchange factor activating the small GTPases Rag. Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated. When complexed to BIRC5, interferes with apoptosome assembly, preventing recruitment of pro-caspase-9 to oligomerized APAF1, thereby selectively suppressing apoptosis initiated via the mitochondrial/cytochrome c pathway. Down-regulates hepatitis B virus (HBV) replication.[1] [2]
Publication Abstract from PubMed
Ragulator is a pentamer composed of p18, MP1, p14, C7orf59, and hepatitis B virus X-interacting protein (HBXIP; LAMTOR 1-5) which acts as a lysosomal scaffold of the Rag GTPases in the amino acid sensitive branch of TORC1 signaling. Here, we present the crystal structure of human HBXIP-C7orf59 dimer (LAMTOR 4/5) at 2.9 A and identify a phosphorylation site on C7orf59 which modulates its interaction with p18. Additionally, we demonstrate the requirement of HBXIP-C7orf59 to stabilize p18 and allow further binding of MP1-p14. The structure of the dimer revealed an unfolded N terminus in C7orf59 (residues 1-15) which was shown to be essential for p18 binding. Full-length p18 does not interact stably with MP1-p14 in the absence of HBXIP-C7orf59, but deletion of p18 residues 108-161 rescues MP1-p14 binding. C7orf59 was phosphorylated by protein kinase A (PKA) in vitro and mutation of the conserved Ser67 residue to aspartate prevented phosphorylation and negatively affected the C7orf59 interaction with p18 both in cell culture and in vitro. C7orf59 Ser67 was phosphorylated in human embryonic kidney 293T cells. PKA activation with forskolin induced dissociation of p18 from C7orf59, which was prevented by the PKA inhibitor H-89. Our results highlight the essential role of HBXIP-C7orf59 dimer as a nucleator of pentameric Ragulator and support a sequential model of Ragulator assembly in which HBXIP-C7orf59 binds and stabilizes p18 which allows subsequent binding of MP1-p14.
C7orf59/LAMTOR4 phosphorylation and structural flexibility modulate Ragulator assembly.,Rasheed N, Lima TB, Mercaldi GF, Nascimento AFZ, Silva ALS, Righetto GL, Bar-Peled L, Shen K, Sabatini DM, Gozzo FC, Aparicio R, Smetana JHC FEBS Open Bio. 2019 Jul 17. doi: 10.1002/2211-5463.12700. PMID:31314152[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Marusawa H, Matsuzawa S, Welsh K, Zou H, Armstrong R, Tamm I, Reed JC. HBXIP functions as a cofactor of survivin in apoptosis suppression. EMBO J. 2003 Jun 2;22(11):2729-40. PMID:12773388 doi:10.1093/emboj/cdg263
- ↑ Bar-Peled L, Schweitzer LD, Zoncu R, Sabatini DM. Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1. Cell. 2012 Sep 14;150(6):1196-208. doi: 10.1016/j.cell.2012.07.032. PMID:22980980 doi:10.1016/j.cell.2012.07.032
- ↑ Rasheed N, Lima TB, Mercaldi GF, Nascimento AFZ, Silva ALS, Righetto GL, Bar-Peled L, Shen K, Sabatini DM, Gozzo FC, Aparicio R, Smetana JHC. C7orf59/LAMTOR4 phosphorylation and structural flexibility modulate Ragulator assembly. FEBS Open Bio. 2019 Jul 17. doi: 10.1002/2211-5463.12700. PMID:31314152 doi:http://dx.doi.org/10.1002/2211-5463.12700
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