UMass Chan AffiliationsProgram in Molecular Medicine
Document TypeJournal Article
KeywordsAmino Acids, Peptides, and Proteins
Nucleic Acids, Nucleotides, and Nucleosides
MetadataShow full item record
AbstractmTORC1 controls anabolic and catabolic processes in response to nutrients through the Rag GTPase heterodimer, which is regulated by multiple upstream protein complexes. One such regulator, FLCN-FNIP2, is a GTPase activating protein (GAP) for RagC/D, but despite its important role, how it activates the Rag GTPase heterodimer remains unknown. We used cryo-EM to determine the structure of FLCN-FNIP2 in a complex with the Rag GTPases and Ragulator. FLCN-FNIP2 adopts an extended conformation with two pairs of heterodimerized domains. The Longin domains heterodimerize and contact both nucleotide binding domains of the Rag heterodimer, while the DENN domains interact at the distal end of the structure. Biochemical analyses reveal a conserved arginine on FLCN as the catalytic arginine finger and lead us to interpret our structure as an on-pathway intermediate. These data reveal features of a GAP-GTPase interaction and the structure of a critical component of the nutrient-sensing mTORC1 pathway.
Shen K, Rogala KB, Chou HT, Huang RK, Yu Z, Sabatini DM. Cryo-EM Structure of the Human FLCN-FNIP2-Rag-Ragulator Complex. Cell. 2019 Nov 27;179(6):1319-1329.e8. doi: 10.1016/j.cell.2019.10.036. Epub 2019 Nov 6. PMID: 31704029. Link to article on publisher's site