Structure of the nutrient-sensing hub GATOR2

Valenstein, Max L.; Rogala, Kacper B.; Lalgudi, Pranav V.; Brignole, Edward J.; Gu, Xin; Saxton, Robert A.; Chantranupong, Lynne; Kolibius, Jonas; Quast, Jan-Philipp; Sabatini, David M.

doi:10.1038/s41586-022-04939-z

Cited by 46 publications

(38 citation statements)

References 62 publications

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“…Restimulation with all amino acids or leucine alone reduced the interaction of WDR59 with SESN2 to 82% and 95%, whereas the interaction with NPRL3 was enhanced to 1.2- and 1.89-fold, respectively. These observations are in line with previous publications [ 4 , [10] , [11] , [12] ]. Surprisingly, restimulation with all amino acids or leucine resulted in a decrease in the interaction between WDR59 and MIOS (85% and 60%), as well as between WDR59 and WDR24 (71% and 65%).…”

Section: Representative Resultssupporting

confidence: 94%

“…The endogenous interaction between WDR59 and SESN2, however, has not been addressed yet. It cannot be ruled out that SESN2 dissociates from WDR24 rather than from WDR59 upon leucine restimulation, however, our results strongly suggest that the endogenous integrity of the GATOR2 complex, especially in distinct metabolic conditions is more complex than described [12] .…”

Section: Conclusion/discussionmentioning

confidence: 54%

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Selection-free endogenous tagging of cell lines by bicistronic co-expression of the surface antigen NGFR

et al. 2022

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Section: Representative Resultssupporting

confidence: 94%

Section: Conclusion/discussionmentioning

confidence: 54%

Selection-free endogenous tagging of cell lines by bicistronic co-expression of the surface antigen NGFR

et al. 2022

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“…This domain layout is similar to the COPI subunits α and β’, confirming earlier predictions (Avidor-Reiss et al, 2004; van Dam et al, 2013; Jékely and Arendt, 2006; Quidwai et al, 2021; Taschner et al, 2012). Our structure shows that IFT121 also has a degenerate RING finger within its C-terminal domain (CTD) (Figure 2A,B), echoing COPI, HOPS, CORVET, and GATOR2 (Hunter et al, 2017; Kaur and Subramanian, 2015; Valenstein et al, 2022). In IFT121, the RING finger domain mediates interaction with IFT43 (Figure 2B) and mutations at this interface are associated with cranioectodermal dysplasia (see Figure S3 for mapping of these and other human disease-causing mutations in the complex, curated in Table S3).…”

Section: Resultsmentioning

confidence: 96%

IFT-A Structure Reveals Carriages for Membrane Protein Transport into Cilia

Hesketh

Mukhopadhyay

Nakamura

et al. 2022

Preprint

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Intraflagellar transport (IFT) trains are molecular machines that traffic proteins between cilia and the cell body. With a molecular weight over 80 MDa, each IFT train is a dynamic polymer of two large complexes (IFT-A and -B) and motor proteins, posing a formidable challenge to mechanistic understanding. Here, we reconstituted the complete human IFT-A complex and obtained its structure using cryo-EM. Combined with AlphaFold prediction and genome-editing studies, our results illuminate how IFT-A polymerizes; interacts with IFT-B; and uses an array of beta-propeller and TPR domains to create "carriages" of the IFT train that engage TULP adaptor proteins. We show that IFT-A:TULP carriages are essential for cilia localization of diverse membrane proteins, as well as ICK - the key kinase regulating IFT train turnaround. These data establish a structural link between IFT-A's distinct functions, provide a blueprint for the IFT-A train, and shed light on how IFT evolved from a proto-coatomer ancestor.

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“…During revision of this manuscript, the cryo-EM structure of the human GATOR2 complex was published 32 . GATOR2 has a structure virtually identical to the SEAC core (SEACAT) (Extended Data Fig.…”

Section: Model Of the Seac On The Vacuolementioning

confidence: 99%

Cryo-EM structure of the SEA complex

Tafur

Hinterndorfer

Gabus

et al. 2022

Nature

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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 yeast1. Functionally, the SEAC has been divided into two subcomplexes: SEACIT, which has GAP activity and inhibits TORC1, and SEACAT, which regulates SEACIT2. This system is conserved in mammals: the GATOR complex, consisting of GATOR1 (SEACIT) and GATOR2 (SEACAT), transmits amino acid3 and glucose4 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.

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Structure of the nutrient-sensing hub GATOR2

Cited by 46 publications

References 62 publications

Selection-free endogenous tagging of cell lines by bicistronic co-expression of the surface antigen NGFR

Selection-free endogenous tagging of cell lines by bicistronic co-expression of the surface antigen NGFR

IFT-A Structure Reveals Carriages for Membrane Protein Transport into Cilia

Cryo-EM structure of the SEA complex

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