SEA you later alli-GATOR – a dynamic regulator of the TORC1 stress response pathway

Abstract

Cells constantly adapt to various environmental changes and stresses. The way in which nutrient and stress levels in a cell feed back to control metabolism and growth are, unsurprisingly, extremely complex, as responding with great sensitivity and speed to the 'feast or famine, slack or stress' status of its environment is a central goal for any organism. The highly conserved target of rapamycin complex 1 (TORC1) controls eukaryotic cell growth and response to a variety of signals, including nutrients, hormones and stresses, and plays the key role in the regulation of autophagy. A lot of attention has been paid recently to the factors in this pathway functioning upstream of TORC1. In this Commentary, we focus on a major, newly discovered upstream regulator of TORC1 -the multiprotein SEA complex, also known as GATOR. We describe the structural and functional features of the yeast complex and its mammalian homolog, and their involvement in the regulation of the TORC1 pathway and TORC1-independent processes. We will also provide an overview of the consequences of GATOR deregulation in cancer and other diseases.

GATOR1 complex: the common genetic actor in focal epilepsies

“…Longin domains are usually found in guanine nucleotide exchange factor (GEF) proteins; however, a GEF activity has not yet been demonstrated for these two proteins 56–58. On the other hand, PEST motifs are often found in rapidly degraded proteins, although these are not well conserved in mammals and could not elicit this function in NPRL2/3 11 14. No three-dimensional (3D) map of the GATOR1 complex is available at present, but a recently published combination of biochemical and computational approaches has revealed the first 3D map of the yeast homologue of the mammalian GATOR complex, in which the two homologous subcomplexes form connected discrete modules, suggesting similar interactions between GATOR1 and GATOR2 14 59.…”

“…The DEP domain, which was named after the initials of the proteins Disheveled, Egl-10 and Pleckstrin, is a globular domain found in numerous GTPase activating proteins. The DEP domain is also found in DEPTOR (a subunit of mTORC1) where it has a role in the interaction between RGS (regulator of G protein signalling) proteins and their membrane-bound G-protein-coupled receptors 14 55 . NPRL2 and NPRL3 are located on chromosomes 3p21.3 and 16p13.3 and encode two proteins of 380 and 569 amino acids, respectively.…”

“…NPRL2 and NPRL3 are located on chromosomes 3p21.3 and 16p13.3 and encode two proteins of 380 and 569 amino acids, respectively. Both proteins are characterised by N-terminal longin domains and PEST motifs 14. Longin domains are usually found in guanine nucleotide exchange factor (GEF) proteins; however, a GEF activity has not yet been demonstrated for these two proteins 56–58.…”

“…10–13 The former includes DEPDC5 (DEP domain-containing protein 5), NPRL2 (nitrogen permease regulator 2-like protein) and NPRL3 (nitrogen permease regulator 3-like protein) proteins, the latter MIOS (missing oocyte, meiosis regulator, homologue), SEH1L (SEH1 like), SEC13 (SEC13 homologue), WDR24 (WD repeat domain 24) and WDR59 (WD repeat domain 59). The role of each protein in these complexes has still to be fully clarified, but the conservation of the mTOR pathway architecture across different species suggests that each partner of the complex carries out fundamental functions 14. Recently, mutations in the genes encoding the components of the GATOR1 subcomplex have been associated with several genetic focal epilepsy (FE) syndromes, including autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE, MIM 600513), recently renamed as autosomal-dominant sleep-related hypermotor epilepsy;15 epilepsy with auditory features (EAF, also known as lateral temporal lobe epilepsy, TLE, MIM 600512); familial FE with variable foci (FFEVF, MIM 604364) 16–20 .…”

TOR Signaling in Budding Yeast

“…Orthologs of components in SEACAT also exist in Drosophila and mammals, that is, WDR24, WDR59, Mios, Seh1L, and Sec13 in flies and humans, respectively, are Sea2, Sea3, Sea4, Seh1, and Sec13 in yeast, and this complex is referred to as GATOR2. All components in SEACAT and GATOR2 contain beta propeller-forming WD40 motifs, which are characteristic in membrane-coating proteins [51]. Sec13 is a component of COPII, which controls vesicle transport.…”