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Hamartin

Non-catalytic component of the TSC-TBC complex, a multiprotein complex that acts as a negative regulator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule biosynthesis to promote cellular biomass generation and growth^1,2,3,4,5,6. The TSC-TBC complex acts as a GTPase-activating protein (GAP) for the small GTPase RHEB, a direct activator of the protein kinase activity of mTORC1^7,8,9. In absence of nutrients, the TSC-TBC complex inhibits mTORC1, thereby preventing phosphorylation of ribosomal protein S6 kinase (RPS6KB1 and RPS6KB2) and EIF4EBP1 (4E-BP1) by the mTORC1 signaling^10,11,12,13. The TSC-TBC complex is inactivated in response to nutrients, relieving inhibition of mTORC1^14,15. Within the TSC-TBC complex, TSC1 stabilizes TSC2 and prevents TSC2 self-aggregation^16,17. Acts as a tumor suppressor¹⁸. Involved in microtubule-mediated protein transport via its ability to regulate mTORC1 signaling (By similarity). Also acts as a co-chaperone for HSP90AA1 facilitating HSP90AA1 chaperoning of protein clients such as kinases, TSC2 and glucocorticoid receptor NR3C1¹⁹. Increases ATP binding to HSP90AA1 and inhibits HSP90AA1 ATPase activity²⁰. Competes with the activating co-chaperone AHSA1 for binding to HSP90AA1, thereby providing a reciprocal regulatory mechanism for chaperoning of client proteins²¹. Recruits TSC2 to HSP90AA1 and stabilizes TSC2 by preventing the interaction between TSC2 and ubiquitin ligase HERC1^22,23.

AlphaFold DB , UniProt , Accession Q92574, Species HUMAN (Homo sapiens, Human), Gene TSC1, Length 1,164 aa.