Journal Article

Cryo-EM structure of the SEA complex

Gabus, Caroline, Sadian, Yashar, Loewith, Robbie, Hamdi, Farzad, Tafur, Lucas, Bergmann, Ariane, Kyrilis, Fotis L., Lamanna, Chiara, Kastritis, Panagiotis L., Hinterndorfer, Kerstin

2022

Overview

The SEA complex (SEAC) is a growth regulator that acts as a GTPase-activating protein (GAP) towards Gtr1, a Rag GTPase that relays nutrient status to the Target of Rapamycin Complex 1 (TORC1) in yeast 1 . Functionally, the SEAC has been divided into two subcomplexes: SEACIT, which has GAP activity and inhibits TORC1, and SEACAT, which regulates SEACIT 2 . This system is conserved in mammals: the GATOR complex, consisting of GATOR1 (SEACIT) and GATOR2 (SEACAT), transmits amino acid 3 and glucose 4 signals to mTORC1. Despite its importance, the structure of SEAC/GATOR, and thus molecular understanding of its function, is lacking. Here, we solve the cryo-EM structure of the native eight-subunit SEAC. The SEAC has a modular structure in which a COPII-like cage corresponding to SEACAT binds two flexible wings, which correspond to SEACIT. The wings are tethered to the core via Sea3, which forms part of both modules. The GAP mechanism of GATOR1 is conserved in SEACIT, and GAP activity is unaffected by SEACAT in vitro. In vivo, the wings are essential for recruitment of the SEAC to the vacuole, primarily via the EGO complex. Our results indicate that rather than being a direct inhibitor of SEACIT, SEACAT acts as a scaffold for the binding of TORC1 regulators. The cryo-EM structure of the yeast SEA complex suggests that SEACAT functions as a scaffold for binding TORC1 regulators.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/28 / 14/35 / 14/63 / 631/45/535/1258/1259 / 631/535/1258/1259 / 631/80/83/2359 / 631/80/86/2369 / Amino Acids / Animals / COP-Coated Vesicles - chemistry / COP-Coated Vesicles - metabolism / Cryoelectron Microscopy / Flexible wings / Glucose / Growth regulators / GTP Phosphohydrolases - chemistry / GTP Phosphohydrolases - metabolism / GTP Phosphohydrolases - ultrastructure / GTPase-activating protein / GTPase-Activating Proteins - chemistry / GTPase-Activating Proteins - metabolism / GTPase-Activating Proteins - ultrastructure / Humanities and Social Sciences / Mammals / Mechanistic Target of Rapamycin Complex 1 - metabolism / Modular structures / Molecular structure / multidisciplinary / Multienzyme Complexes - chemistry / Multienzyme Complexes - metabolism / Multienzyme Complexes - ultrastructure / Nutrient status / Protein Subunits - chemistry / Protein Subunits - metabolism / Proteins / Rapamycin / Saccharomyces cerevisiae - chemistry / Saccharomyces cerevisiae - metabolism / Saccharomyces cerevisiae Proteins - chemistry / Saccharomyces cerevisiae Proteins - metabolism / Saccharomyces cerevisiae Proteins - ultrastructure / Science / Science (multidisciplinary) / TOR protein / Yeast