An evolutionary mechanism to assimilate new nutrient sensors into the mTORC1 pathway

Grace Y. Liu (), Patrick Jouandin, Raymond E. Bahng, Norbert Perrimon () and David M. Sabatini ()
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Grace Y. Liu: Department of Biology
Patrick Jouandin: Blavatnik Institute, Harvard Medical School
Raymond E. Bahng: Department of Biology
Norbert Perrimon: Blavatnik Institute, Harvard Medical School
David M. Sabatini: Institute of Organic Chemistry and Biochemistry

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-46680-3

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