Animals sense and respond to nutrient availability in their environments, a task coordinated in part by the mTOR complex 1 (mTORC1) pathway. mTORC1 regulates growth in response to nutrients and, in mammals, senses specific amino acids through specialized sensors that bind the GATOR1/2 signaling hub. Given that animals can occupy diverse niches, we hypothesized that the pathway might evolve distinct sensors in different metazoan phyla. Whether such customization occurs, and how the mTORC1 pathway might capture new inputs, is unknown. Here, we identify the Drosophila melanogaster protein Unmet expectations (CG11596) as a species-restricted methionine sensor that directly binds the fly GATOR2 complex in a fashion antagonized by S-adenosylmethionine (SAM). We find that in Dipterans GATOR2 rapidly evolved the capacity to bind Unmet and to thereby repurpose a previously independent methyltransferase as a SAM sensor. Thus, the modular architecture of the mTORC1 pathway allows it to co-opt preexisting enzymes to expand its nutrient sensing capabilities, revealing a mechanism for conferring evolvability on an otherwise conserved system.

Department of Biology Massachusetts Institute of Technology 77 Massachusetts Avenue Cambridge MA USA

Department of Genetics Blavatnik Institute Harvard Medical School Boston MA USA

Howard Hughes Medical Institute Harvard Medical School Boston MA USA

Institut de Recherche en Cancérologie de Montpellier Inserm U1194 UM ICM Campus Val d'Aurelle Montpellier Cedex 5 France

Institute of Organic Chemistry and Biochemistry Flemingovo n 2 166 10 Praha 6 Prague Czech Republic

Koch Institute for Integrative Cancer Research and Massachusetts Institute of Technology Department of Biology 77 Massachusetts Avenue Cambridge MA USA

Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology Department of Biology 455 Main Street Cambridge MA USA

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bioRxiv. 2023 May 26:2023.05.25.541239. doi: 10.1101/2023.05.25.541239. PubMed

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Structural basis for the dynamic regulation of mTORC1 by amino acids