Cryo-EM Structure of the Human FLCN-FNIP2-Rag-Ragulator Complex.

Kuang ShenΨ, Kacper B RogalaΨ, Hui-Ting Chou, Rick K Huang, Zhiheng Yu, David M Sabatini

Cell. 179(6):1319-1329.e8. 2019 November 27.

blue & bold — Rogala Lab member
Ψ — equal contribution
@ — corresponding author

mTORC1 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.


PubMed: 31704029 // Journal website [open access]

Deposited structures: 6ULG

Deposited cryo-EM maps: EMD-20814


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Dispatch article [open access] in Current Biology by Wei Peng and Jenna Jewell.