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TitleCryo-EM Structure of the Human FLCN-FNIP2-Rag-Ragulator Complex.
Journal, issue, pagesCell, Vol. 179, Issue 6, Page 1319-11329.e8, Year 2019
Publish dateNov 27, 2019
AuthorsKuang Shen / Kacper B Rogala / Hui-Ting Chou / Rick K Huang / Zhiheng Yu / David M Sabatini /
PubMed 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- ...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.
External linksCell / PubMed:31704029 / PubMed Central
MethodsEM (single particle)
Resolution3.31 Å
Structure data

EMDB-20814, PDB-6ulg:
Cryo-EM structure of the FLCN-FNIP2-Rag-Ragulator complex
Method: EM (single particle) / Resolution: 3.31 Å

Chemicals

ChemComp-GDP:
GUANOSINE-5'-DIPHOSPHATE / GDP, energy-carrying molecule*YM

ChemComp-GNP:
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / GppNHp, GMPPNP, energy-carrying molecule analogue*YM

ChemComp-MG:
Unknown entry

Source
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN / FLCN-FNIP2 / Rag GTPases / Ragulator

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