8fw5
Chimeric HsGATOR1-SpGtr-SpLam complex
Structural highlights
DiseaseDEPD5_HUMAN Rolandic epilepsy;Autosomal dominant nocturnal frontal lobe epilepsy;Autosomal dominant epilepsy with auditory features;Familial focal epilepsy with variable foci. The disease is caused by mutations affecting the gene represented in this entry. Inactivating mutations and truncating deletions in the genes encoding GATOR1 proteins, including DEPDC5, are detected in glioblastoma and ovarian tumors and are associated with loss of heterozygosity events. Inactivation of GATOR1 proteins promotes constitutive localization of mTORC1 to the lysosomal membrane and blocks mTORC1 inactivation following amino acid withdrawal (PubMed:23723238).[1] FunctionDEPD5_HUMAN As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the TORC1 pathway. The GATOR1 complex strongly increases GTP hydrolysis by RRAGA and RRAGB within RRAGC-containing heterodimers, thereby deactivating RRAGs, releasing mTORC1 from lysosomal surface and inhibiting mTORC1 signaling. The GATOR1 complex is negatively regulated by GATOR2 the other GATOR subcomplex in this amino acid-sensing branch of the TORC1 pathway.[2] [3] Publication Abstract from PubMedmTORC1 is a protein kinase complex that controls cellular growth in response to nutrient availability. Amino acid signals are transmitted toward mTORC1 via the Rag/Gtr GTPases and their upstream regulators. An important regulator is LAMTOR, which localizes Rag/Gtr on the lysosomal/vacuole membrane. In human cells, LAMTOR consists of five subunits, but in yeast, only three or four. Currently, it is not known how variation of the subunit stoichiometry may affect its structural organization and biochemical properties. Here, we report a 3.1 A-resolution structural model of the Gtr-Lam complex in Schizosaccharomyces pombe. We found that SpGtr shares conserved architecture as HsRag, but the intersubunit communication that coordinates nucleotide loading on the two subunits differs. In contrast, SpLam contains distinctive structural features, but its GTP-specific GEF activity toward SpGtr is evolutionarily conserved. Our results revealed unique evolutionary paths of the protein components of the mTORC1 pathway. Structure of the Schizosaccharomyces pombe Gtr-Lam complex reveals evolutionary divergence of mTORC1-dependent amino acid sensing.,Tettoni SD, Egri SB, Doxsey DD, Veinotte K, Ouch C, Chang JY, Song K, Xu C, Shen K Structure. 2023 Sep 7;31(9):1065-1076.e5. doi: 10.1016/j.str.2023.06.012. Epub , 2023 Jul 14. PMID:37453417[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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