# SEA and GATOR 10 Years Later
## 4 Structural Features of the SEA and GATOR Complexes  
The overall architecture of SEA/GATOR proteins is evolutionary conserved [3]. DEPDC5 is only 10 amino acid residues longer than Iml1/Sea1, but both have an identical fold arrangement. The human orthologs of Sea2-Sea4, Npr2 and Npr3 are smaller than yeast proteins, mainly because of the deletion of protein regions, predicted to be disordered in yeast. It is quite reasonable to expect that the mammalian GATOR components repertoire would be larger compared to yeast due to the expression of alternative splicing products. For example, bioinformmatical predictions revealed that WDR24 has at least two isoforms, one of which is missing about 130 amino acid residues in the N-terminal part [3]. One of the NPRL3 isoforms that lacks the N-terminal part and is highly expressed in red blood cells has just recently been characterized [25]. A splicing variant that led to exon 3 skipping in _NPRL2_ was detected in an individual with familial focal epilepsy (see below) [26].  
Two subcomplexes of the SEA/GATOR are very different structurally (Figure 2). SEACIT/GATOR1 members have domains, found in proteins that control the functions of small GTPases. SEACAT/GATOR2 components are enriched with domains found in coating assemblies (i.e., COPI and COPII coated vesicles, nuclear pore complex, etc.) (see below). Seh1, Sec13 and the N-termini of Sea4 and Sea2 in _S. cerevisiae_ SEACAT appear to form a large cluster of \(\beta\)-propeller domains. Similar arrangements of \(\beta\)-propeller domains have been described at the vertex of the evolutionarily related complexes COPI and COPII [27].  
In yeast, SEACAT and SEACIT interact to form the full SEA complex (Figure 1) [13]. A 3D map of the _S. cerevisiae_ SEA complex, obtained by a combination of biochemical and computational approaches, suggests that SEACAT and SEACIT are connected by interactions between the N-termini of Sea3 from SEACAT and both Npr3 and Iml1/Sea1 from SEACIT [13]. Similar observations have recently been made in _S. pombe_, where Sea3 anchors other GATOR2 components to GATOR1, although, as expected, Sea3 was not required for the assembly of GATOR1 components [28]. In humans, GATOR1 and GATOR2 do not form a stable GATOR complex [12], yet, similar to yeast, NPRL3 is necessary and sufficient for the interaction with GATOR2 [29].  
Despite the considerable progress in the structural determination of the constituents of the mTOR1 pathway that have been made in the last five years [30], only the structure of human GATOR1 has been solved (Figure 2A). All structural information that is currently available for GATOR2 or for the yeast SEA complex comes from bioinformatic predictions and interactivity assays [3,13]. The lack of high-resolution structures of the GATOR2 and of the entire complex both in yeast and humans are among the major reasons that prevent our full understanding of the SEA/GATOR functions at the present.  
Figure 2: Domain organization of GATOR1 and GATOR2 proteins. (**A**) Domain structure and interaction of GATOR1 proteins (top); atomic model of GATOR1 complex (PDB:6 CET), adapted from [29] and modified by PyMOL (bottom left) and cartoon representation of GATOR1 structure with domains indicated (bottom right). (**B**) Schematic representation of GATOR2 components, with domain boundaries according to secondary structure predictions from [3].