Amino acid sensing and lysosomal signaling complexes.

Zhicheng Cui, Aaron M N Joiner, Rachel M Jansen, James H Hurley

Journal: Current opinion in structural biology 2023;79():102544

PMID: 36804703

Free Full Text on Elsevier Science View on PubMed

Abstract

Amino acid pools in the cell are monitored by dedicated sensors, whose structures are now coming into view. The lysosomal Rag GTPases are central to this pathway, and the regulation of their GAP complexes, FLCN-FNIP and GATOR1, have been worked out in detail. For FLCN-FNIP, the entire chain of events from the arginine transporter SLC38A9 to substrate-specific mTORC1 activation has been visualized. The structure GATOR2 has been determined, hinting at an ordering of amino acid signaling across a larger size scale than anticipated. The centerpiece of lysosomal signaling, mTORC1, has been revealed to recognize its substrates by more nuanced and substrate-specific mechanisms than previous appreciated. Beyond the well-studied Rag GTPase and mTORC1 machinery, another lysosomal amino acid sensor/effector system, that of PQLC2 and the C9orf72-containing CSW complex, is coming into structural view. These developments hold promise for further insights into lysosomal physiology and lysosome-centric therapeutics.

Address: Department of Molecular and Cell Biology, University of California Berkeley, Berkeley CA 94720, USA; California Institute for Quantitative Biosciences, University of California, Berkeley, CA, 94720, USA.; Department of Molecular and Cell Biology, University of California Berkeley, Berkeley CA 94720, USA; California Institute for Quantitative Biosciences, University of California, Berkeley, CA, 94720, USA; Helen Wills Neuroscience Institute, University of California, Berkeley, CA 94720, USA. Electronic address: [email protected].

DOI: 10.1016/j.sbi.2023.102544

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https://assays.cancer.gov/CPTAC-1548

MeSH Terms: Amino Acids, Monomeric GTP-Binding Proteins, Signal Transduction, Mechanistic Target of Rapamycin Complex 1, Lysosomes