PMID- 22819219
OWN - NLM
STAT- MEDLINE
DCOM- 20130122
LR  - 20211203
IS  - 1878-4186 (Electronic)
IS  - 0969-2126 (Linking)
VI  - 20
IP  - 9
DP  - 2012 Sep 5
TI  - An autoinhibited noncanonical mechanism of GTP hydrolysis by Rheb maintains 
      mTORC1 homeostasis.
PG  - 1528-39
LID - 10.1016/j.str.2012.06.013 [doi]
AB  - Rheb, an activator of mammalian target of rapamycin (mTOR), displays low 
      intrinsic GTPase activity favoring the biologically activated, GTP-bound state. 
      We identified a Rheb mutation (Y35A) that increases its intrinsic nucleotide 
      hydrolysis activity  approximately 10-fold, and solved structures of both its active and 
      inactive forms, revealing an unexpected mechanism of GTP hydrolysis involving 
      Asp65 in switch II and Thr38 in switch I. In the wild-type protein this 
      noncanonical mechanism is markedly inhibited by Tyr35, which constrains the 
      active site conformation, restricting the access of the catalytic Asp65 to the 
      nucleotide-binding pocket. Rheb Y35A mimics the enthalpic and entropic changes 
      associated with GTP hydrolysis elicited by the GTPase-activating protein (GAP) 
      TSC2, and is insensitive to further TSC2 stimulation. Overexpression of Rheb Y35A 
      impaired the regulation of mTORC1 signaling by growth factor availability. We 
      demonstrate that the opposing functions of Tyr35 in the intrinsic and 
      GAP-stimulated GTP catalysis are critical for optimal mTORC1 regulation.
CI  - Copyright (c) 2012 Elsevier Ltd. All rights reserved.
FAU - Mazhab-Jafari, Mohammad T
AU  - Mazhab-Jafari MT
AD  - Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 
      2M9, Canada.
FAU - Marshall, Christopher B
AU  - Marshall CB
FAU - Ishiyama, Noboru
AU  - Ishiyama N
FAU - Ho, Jason
AU  - Ho J
FAU - Di Palma, Vanessa
AU  - Di Palma V
FAU - Stambolic, Vuk
AU  - Stambolic V
FAU - Ikura, Mitsuhiko
AU  - Ikura M
LA  - eng
SI  - PDB/3SEA
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20120719
PL  - United States
TA  - Structure
JT  - Structure (London, England : 1993)
JID - 101087697
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Neuropeptides)
RN  - 0 (Proteins)
RN  - 0 (Ras Homolog Enriched in Brain Protein)
RN  - 0 (Rheb protein, mouse)
RN  - 86-01-1 (Guanosine Triphosphate)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.6.5.2 (Monomeric GTP-Binding Proteins)
SB  - IM
MH  - Amino Acid Motifs
MH  - Amino Acid Substitution
MH  - Animals
MH  - Catalytic Domain
MH  - Crystallography, X-Ray
MH  - Enzyme Activation
MH  - Guanosine Triphosphate/*chemistry/metabolism
MH  - HEK293 Cells
MH  - HeLa Cells
MH  - Homeostasis
MH  - Humans
MH  - Hydrogen Bonding
MH  - Hydrolysis
MH  - Kinetics
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Models, Molecular
MH  - Monomeric GTP-Binding Proteins/*chemistry/genetics/metabolism
MH  - Multiprotein Complexes
MH  - Mutagenesis, Site-Directed
MH  - Neuropeptides/*chemistry/genetics/metabolism
MH  - Protein Binding
MH  - Proteins/*metabolism
MH  - Ras Homolog Enriched in Brain Protein
MH  - Ribosomal Protein S6 Kinases, 70-kDa/metabolism
MH  - TOR Serine-Threonine Kinases
MH  - Thermodynamics
EDAT- 2012/07/24 06:00
MHDA- 2013/01/23 06:00
CRDT- 2012/07/24 06:00
PHST- 2011/10/25 00:00 [received]
PHST- 2012/06/18 00:00 [revised]
PHST- 2012/06/20 00:00 [accepted]
PHST- 2012/07/24 06:00 [entrez]
PHST- 2012/07/24 06:00 [pubmed]
PHST- 2013/01/23 06:00 [medline]
AID - S0969-2126(12)00247-X [pii]
AID - 10.1016/j.str.2012.06.013 [doi]
PST - ppublish
SO  - Structure. 2012 Sep 5;20(9):1528-39. doi: 10.1016/j.str.2012.06.013. Epub 2012 
      Jul 19.