Short name: Tuberin
Overlapping homologous superfamilies
- Tuberin/Ral GTPase-activating protein subunit alpha (IPR027107)
- Tuberin (IPR003913)
Tuberous sclerosis (TSC) is an autosomal dominant disorder caused by a mutation in either the TSC1 or TSC2 tumour suppressor genes. The disease is characterised by hamartomas in one or more organs (including brain, skin, heart and kidney) giving rise to a broad phenotypic spectrum (including seizures, mental retardation, renal dysfunction and dermatological abnormalities. TSC2 encodes tuberin, a putative GTPase activating protein for rap1 and rab5. The TSC1 gene was recently identified and codes for hamartin, a novel protein with no significant similarity to tuberin or any other known vertebrate protein [PMID: 9580671]. Hamartin and tuberin have been shown to associate physically in vivo, their interaction being mediated by predicted coiled-coil domains. It is thought that hamartin and tuberin function in the same complex, rather than in separate pathways. Moreover, because oligomerisation of the hamartin C-terminal coiled coil domain is inhibited by the presence of tuberin, it is possible that tuberin acts as a chaperone, preventing hamartin self-aggregation [PMID: 9580671].
Tuberin is a widely expressed 1784-amino-acid protein. Expression of the wild-type gene in TSC2 mutant tumour cells inhibits proliferation and tumorigenicity. This "suppressor" activity is encoded by a functional domain in the C terminus that shares similarity with the GTPase activating protein Rap1GAP [PMID: 7558029]. It is thought that tuberin functions as a Rab5GAP in vivo to negatively regulate Rab5-GTP activity in endocytosis [PMID: 9045618]. It also acts as a GTPase-activating protein (GAP) for the small GTPase RheB, a direct activator of the protein kinase activity of mTORC1 [PMID: 12271141, PMID: 15340059].
- PR01431 (TUBERIN)