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Cryo-EM Structure of the Human FLCN-FNIP2-Rag-Ragulator Complex.
- Source :
-
Cell [Cell] 2019 Nov 27; Vol. 179 (6), pp. 1319-1329.e8. Date of Electronic Publication: 2019 Nov 06. - Publication Year :
- 2019
-
Abstract
- 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.<br /> (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Subjects :
- Arginine metabolism
Biocatalysis
Carrier Proteins chemistry
GTPase-Activating Proteins metabolism
HEK293 Cells
Humans
Hydrolysis
Models, Molecular
Monomeric GTP-Binding Proteins chemistry
Multiprotein Complexes chemistry
Protein Conformation
Protein Multimerization
Proto-Oncogene Proteins chemistry
Tumor Suppressor Proteins chemistry
Carrier Proteins ultrastructure
Cryoelectron Microscopy
Monomeric GTP-Binding Proteins ultrastructure
Multiprotein Complexes ultrastructure
Proto-Oncogene Proteins ultrastructure
Tumor Suppressor Proteins ultrastructure
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4172
- Volume :
- 179
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Cell
- Publication Type :
- Academic Journal
- Accession number :
- 31704029
- Full Text :
- https://doi.org/10.1016/j.cell.2019.10.036