Identification of regions critical for the integrity of the TSC1-TSC2-TBC1D7 complex

Arthur Jorge Santiago Lima; Marianne Hoogeveen-Westerveld; Akio Nakashima; Anneke Maat-Kievit; Ans van den Ouweland; Dicky Halley; Ushio Kikkawa; Mark Nellist

doi:10.1371/journal.pone.0093940

Identification of regions critical for the integrity of the TSC1-TSC2-TBC1D7 complex

PLoS One. 2014 Apr 8;9(4):e93940. doi: 10.1371/journal.pone.0093940. eCollection 2014.

Authors

Arthur Jorge Santiago Lima¹, Marianne Hoogeveen-Westerveld¹, Akio Nakashima², Anneke Maat-Kievit¹, Ans van den Ouweland¹, Dicky Halley¹, Ushio Kikkawa², Mark Nellist¹

Affiliations

¹ Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
² Biosignal Research Center, Kobe University, Kobe, Japan.

Abstract

The TSC1-TSC2-TBC1D7 complex is an important negative regulator of the mechanistic target of rapamycin complex 1 that controls cell growth in response to environmental cues. Inactivating TSC1 and TSC2 mutations cause tuberous sclerosis complex (TSC), an autosomal dominant disorder characterised by the occurrence of benign tumours in various organs and tissues, notably the brain, skin and kidneys. TBC1D7 mutations have not been reported in TSC patients but homozygous inactivation of TBC1D7 causes megaencephaly and intellectual disability. Here, using an exon-specific deletion strategy, we demonstrate that some regions of TSC1 are not necessary for the core function of the TSC1-TSC2 complex. Furthermore, we show that the TBC1D7 binding site is encoded by TSC1 exon 22 and identify amino acid residues involved in the TSC1-TBC1D7 interaction.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carrier Proteins / genetics*
Carrier Proteins / metabolism
Exons
Humans
Intracellular Signaling Peptides and Proteins
Mutation
Tuberous Sclerosis / genetics*
Tuberous Sclerosis / metabolism
Tuberous Sclerosis Complex 1 Protein
Tuberous Sclerosis Complex 2 Protein
Tumor Suppressor Proteins / genetics*
Tumor Suppressor Proteins / metabolism

Substances

Carrier Proteins
Intracellular Signaling Peptides and Proteins
TBC1D7 protein, human
TSC1 protein, human
TSC2 protein, human
Tuberous Sclerosis Complex 1 Protein
Tuberous Sclerosis Complex 2 Protein
Tumor Suppressor Proteins

Grants and funding

The study was supported by the Department of Clinical Genetics, Erasmus MC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.