| Structural highlights
6ehr is a 7 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Related: | 6ehp |
| Gene: | LAMTOR3, MAP2K1IP1, MAPKSP1, PRO2783 (HUMAN), LAMTOR2, MAPBPIP, ROBLD3, HSPC003 (HUMAN), LAMTOR5, HBXIP, XIP (HUMAN), LAMTOR4, C7orf59 (HUMAN), LAMTOR1, C11orf59, PDRO, PP7157 (HUMAN), RRAGA (HUMAN), RRAGC (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[LTOR2_HUMAN] Primary immunodeficiency syndrome due to p14 deficiency. The disease is caused by mutations affecting the gene represented in this entry.
Function
[RRAGA_HUMAN] Guanine nucleotide-binding protein that plays a crucial role in the cellular response to amino acid availability through regulation of the mTORC1 signaling cascade. Forms heterodimeric Rag complexes with RRAGC or RRAGD and cycles between an inactive GDP-bound and an active GTP-bound form. In its active form participates in the relocalization of mTORC1 to the lysosomes and its subsequent activation by the GTPase RHEB. Involved in the RCC1/Ran-GTPase pathway. May play a direct role in a TNF-alpha signaling pathway leading to induction of cell death. May alternatively act as a cellular target for adenovirus E3-14.7K, an inhibitor of TNF-alpha functions, thereby affecting cell death.[1] [2] [3] [4] [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.[5] [LTOR3_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. Adapter protein that enhances the efficiency of the MAP kinase cascade facilitating the activation of MAPK2.[6] [7] [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.[8] [9] [RRAGC_HUMAN] Guanine nucleotide-binding protein forming heterodimeric Rag complexes required for the amino acid-induced relocalization of mTORC1 to the lysosomes and its subsequent activation by the GTPase RHEB. This is a crucial step in the activation of the TOR signaling cascade by amino acids.[10] [LTOR2_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. Adapter protein that enhances the efficiency of the MAP kinase cascade facilitating the activation of MAPK2.[11] [12] [LTOR1_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. LAMTOR1 is directly responsible for anchoring the Ragulator complex to membranes. Also required for late endosomes/lysosomes biogenesis it may regulate both the recycling of receptors through endosomes and the MAPK signaling pathway through recruitment of some of its components to late endosomes. May be involved in cholesterol homeostasis regulating LDL uptake and cholesterol release from late endosomes/lysosomes. May also play a role in RHOA activation.[13] [14] [15] [16]
Publication Abstract from PubMed
LAMTOR (Late endosomal and lysosomal adaptor and mitogen activated protein kinase (MAPK) and mechanistic target of rapamycin (mTOR) activator) also known as "Ragulator," controls the activity of mTOR complex 1 (mTORC1) on the lysosome. The crystal structure of LAMTOR consists of two roadblock/LC7 domain folded heterodimers wrapped and apparently held together by LAMTOR1, which assembles the complex on lysosomes. In addition, the Rag GTPases associated with the pentamer through their C-terminal domains, predefining the orientation for interaction with mTORC1. In vitro reconstitution and experiments with site directed mutagenesis defined the physiological importance of LAMTOR1 in assembling the remaining components to ensure fidelity of mTORC1 signaling. Functional data validated the impact of two short LAMTOR1 amino acid regions in recruitment and stabilization of the Rag GTPases.
Crystal structure of the human lysosomal mTORC1 scaffold complex and its impact on signaling.,de Araujo MEG, Naschberger A, Furnrohr BG, Stasyk T, Dunzendorfer-Matt T, Lechner S, Welti S, Kremser L, Shivalingaiah G, Offterdinger M, Lindner HH, Huber LA, Scheffzek K Science. 2017 Sep 21. pii: eaao1583. doi: 10.1126/science.aao1583. PMID:28935770[17]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell. 2010 Apr 16;141(2):290-303. doi: 10.1016/j.cell.2010.02.024. Epub 2010 Apr , 8. PMID:20381137 doi:10.1016/j.cell.2010.02.024
- ↑ Deng L, Jiang C, Chen L, Jin J, Wei J, Zhao L, Chen M, Pan W, Xu Y, Chu H, Wang X, Ge X, Li D, Liao L, Liu M, Li L, Wang P. The ubiquitination of rag A GTPase by RNF152 negatively regulates mTORC1 activation. Mol Cell. 2015 Jun 4;58(5):804-18. doi: 10.1016/j.molcel.2015.03.033. Epub 2015, Apr 30. PMID:25936802 doi:http://dx.doi.org/10.1016/j.molcel.2015.03.033
- ↑ Li Y, Kang J, Horwitz MS. Interaction of an adenovirus 14.7-kilodalton protein inhibitor of tumor necrosis factor alpha cytolysis with a new member of the GTPase superfamily of signal transducers. J Virol. 1997 Feb;71(2):1576-82. PMID:8995684
- ↑ Hirose E, Nakashima N, Sekiguchi T, Nishimoto T. RagA is a functional homologue of S. cerevisiae Gtr1p involved in the Ran/Gsp1-GTPase pathway. J Cell Sci. 1998 Jan;111 ( Pt 1):11-21. PMID:9394008
- ↑ 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
- ↑ Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell. 2010 Apr 16;141(2):290-303. doi: 10.1016/j.cell.2010.02.024. Epub 2010 Apr , 8. PMID:20381137 doi:10.1016/j.cell.2010.02.024
- ↑ 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
- ↑ 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
- ↑ Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell. 2010 Apr 16;141(2):290-303. doi: 10.1016/j.cell.2010.02.024. Epub 2010 Apr , 8. PMID:20381137 doi:10.1016/j.cell.2010.02.024
- ↑ Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell. 2010 Apr 16;141(2):290-303. doi: 10.1016/j.cell.2010.02.024. Epub 2010 Apr , 8. PMID:20381137 doi:10.1016/j.cell.2010.02.024
- ↑ 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
- ↑ Hoshino D, Tomari T, Nagano M, Koshikawa N, Seiki M. A novel protein associated with membrane-type 1 matrix metalloproteinase binds p27(kip1) and regulates RhoA activation, actin remodeling, and matrigel invasion. J Biol Chem. 2009 Oct 2;284(40):27315-26. doi: 10.1074/jbc.M109.041400. Epub 2009, Aug 4. PMID:19654316 doi:http://dx.doi.org/10.1074/jbc.M109.041400
- ↑ Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell. 2010 Apr 16;141(2):290-303. doi: 10.1016/j.cell.2010.02.024. Epub 2010 Apr , 8. PMID:20381137 doi:10.1016/j.cell.2010.02.024
- ↑ Guillaumot P, Luquain C, Malek M, Huber AL, Brugiere S, Garin J, Grunwald D, Regnier D, Petrilli V, Lefai E, Manie SN. Pdro, a protein associated with late endosomes and lysosomes and implicated in cellular cholesterol homeostasis. PLoS One. 2010 Jun 8;5(6):e10977. doi: 10.1371/journal.pone.0010977. PMID:20544018 doi:http://dx.doi.org/10.1371/journal.pone.0010977
- ↑ 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
- ↑ de Araujo MEG, Naschberger A, Furnrohr BG, Stasyk T, Dunzendorfer-Matt T, Lechner S, Welti S, Kremser L, Shivalingaiah G, Offterdinger M, Lindner HH, Huber LA, Scheffzek K. Crystal structure of the human lysosomal mTORC1 scaffold complex and its impact on signaling. Science. 2017 Sep 21. pii: eaao1583. doi: 10.1126/science.aao1583. PMID:28935770 doi:http://dx.doi.org/10.1126/science.aao1583
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