# SEA and GATOR 10 Years Later
## 6 SEA and GATOR Functions beyond Nutrient Responding  
### SEA/GATOR Evolution Origin  
SEA/GATOR has always been \"living double lives\" with a number of its components having diverse \"moonlighting\" functions beyond their role in the regulation of nutrient sensing and responding (Figures 4 and 5). Although the majority of these functions seem to be related to the SEA/GATOR role in the regulation of mTOR1, others are clearly associated with totally different pathways. Accordingly, despite the fact that the main localization site of SEA/GATOR is a vacuole/lysosomal membrane, some of its components can be found in the nucleus, ER, mitochondria, plasma membrane, etc., depending on the functions that they fulfil in different cell types, stages of cell cycle progression and physiological conditions [24; 54; 94; 135; 137; 138; 139; 140]. The most outstanding examples are Seh1  
Figure 4: Functions of the _S. cerevisiae_ SEA complex and its components beyond nutrient response. Indicated are Seh1 and Sec13 as components of the nuclear pore complex and Sec13 as part of COPII vesicles. Npr2 and Npr3 regulate retrograde signaling. Npr2 is also involved in the regulation of TCA cycle. Finally, SEA complex is involved in the maintenance of the vacuole-mitochondria contact sites (vCLAMP) and is important for mitophagy. and Sec13, which together are the members of the Nup84 subcomplex in the nuclear pore complex, with Sec13 also being a component of COPII coated vesicles [3]. This \"double life\" of Seh1 and \"triple life\" of Sec13 witnesses the evolution of the endomembrane system. Indeed, the progression from prokaryotic to eukaryotic cells was accompanied by the acquisition of membranous structures, eventually transformed into organelles, which often adopted preexisting molecules and adjusted them for new needs via duplication and neofunctionalization [33]. During this transformation, a central role was played by ancient protocoatomers, which facilitated membrane bending. Not only Seh1 and Sec13, but the entire SEACAT/GATOR2 complex belongs to the large family of protocoatomer-derived complexes that form transport vesicles (COPI, COPII, clathrin), membrane-associated coats (nuclear pore complexes), tethering complexes (HOPS/CORVET) and other membrane associated structures, such as SEACAT/GATOR itself [3; 31; 34]. These various assemblies have a number of structural similarities, including a hallmark feature--a presence of N-terminal \(\beta\)-propeller, formed by WD40 repeats, and C-terminal \(\alpha\)-solenoid composed of \(\alpha\)-helices (HEAT repeats). In that view, Sea4/MIOS is the most well preserved protocoatomer descendant, while Sea2/WDR59 and Sea3/WDR24 diverged more profoundly, loosing many \(\alpha\)-helices, but still preserving N-terminal \(\beta\)-propellers. GTPases, with their corresponding GEFs and GAPs, are other important elements of membrane-associated assemblies. SEACIT/GATOR1 carries this functional feature of endomembrane system, being a GAP for RAGA GTPase. In addition, longin domains present in two components of the SEACIT/GATOR1 can also be found in small GTPases and many other proteins involved in assembly, fusion and tethering of membranes [141]. Here, again, paralogs Npr2/NPRL2 and Npr3/NPRL3 evidence that evolution progressed through duplication and divergence, because both proteins seem to have additional functions, apart from mTOR1 regulation. Remarkably, the entire vacuole/lysosome-associated mTOR1 pathway machinery contains multiple structural elements typical for classical endomembrane systems [30]. For example, the mTORC1 complex has a \(\beta\)-propeller subunit mLST8, structurally very close to Seh1 and Sec13. Similar to other coatomers, another mTORC1 subunit, Kog1/RAPTOR, contains HEAT repeats and \(\beta\)-propeller, but in a \"Lego game of evolution\" these structural elements switch places with HEAT repeats situated at the N-terminus and \(\beta\)-propeller at the C-terminus. By the way, in the mTORC1 complex, RAPTOR interacts with the HEAT domain of mTOR.