Pathological mutations in TSC1 and TSC2 disrupt the interaction between hamartin and tuberin

Hodges, Angela K., Li, Shaowei, Maynard, Julie Helen, Parry, Lee ORCID: https://orcid.org/0000-0002-4467-9196, Braverman, Richard, DeClue, Jeffrey E., Cheadle, Jeremy Peter ORCID: https://orcid.org/0000-0001-9453-8458 and Sampson, Julian Roy ORCID: https://orcid.org/0000-0002-2902-2348 2001. Pathological mutations in TSC1 and TSC2 disrupt the interaction between hamartin and tuberin. Human Molecular Genetics 10 (25) , pp. 2899-9205. 10.1093/hmg/10.25.2899

Full text not available from this repository.

Abstract

Critical functions of hamartin and tuberin, encoded by the TSC1 and TSC2 genes, are likely to be closely linked. The proteins interact directly with one another and mutations affecting either gene result in the tuberous sclerosis phenotype. However, the regions of hamartin and tuberin that interact have not been well defined, and the relationship between their interaction and the pathogenesis of tuberous sclerosis has not been explored. To address these issues a series of hamartin and tuberin constructs were used to assay for interaction in the yeast two-hybrid system. Hamartin (amino acids 302–430) and tuberin (amino acids 1–418) interacted strongly with one another. A region of tuberin encoding a putative coiled-coil (amino acids 346–371) was necessary but not sufficient to mediate the interaction with hamartin, as more N-terminal residues were also required. A region of hamartin (amino acids 719–998) predicted to encode coiled-coils was capable of oligermerization but was not important for the interaction with tuberin. Subtle, non-truncating mutations identified in patients with tuberous sclerosis and located within the putative binding regions of hamartin (N198_F199delinsI;593–595delACT) or tuberin (G294E and I365del), abolished or dramatically reduced interaction of the proteins as assessed by yeast two-hybrid assays and by co-immunoprecipitation of the full-length proteins from Cos7 cells. In contrast, three non-pathogenic missense polymorphisms of tuberin (R261W, M286V, R367Q) in the same region as the disease-causing TSC2 mutations did not. These results indicate a requirement for interaction in critical growth suppressing functions of hamartin and tuberin.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences European Cancer Stem Cell Research Institute (ECSCRI) Medicine
Subjects:	R Medicine > R Medicine (General)
Publisher:	Oxford University Press
ISSN:	1460-2083
Last Modified:	17 Oct 2022 08:25
URI:	https://orca.cardiff.ac.uk/id/eprint/104

Citation Data

Cited 106 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item