Q15382 · RHEB_HUMAN
- ProteinGTP-binding protein Rheb
- GeneRHEB
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids184 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Small GTPase that acts as an allosteric activator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule biosynthesis to promote cellular biomass generation and growth (PubMed:12172553, PubMed:12271141, PubMed:12842888, PubMed:12869586, PubMed:12906785, PubMed:15340059, PubMed:15854902, PubMed:16098514, PubMed:20381137, PubMed:22819219, PubMed:24529379, PubMed:29416044, PubMed:32470140, PubMed:33157014).
In response to nutrients, growth factors or amino acids, specifically activates the protein kinase activity of MTOR, the catalytic component of the mTORC1 complex: acts by causing a conformational change that allows the alignment of residues in the active site of MTOR, thereby enhancing the phosphorylation of ribosomal protein S6 kinase (RPS6KB1 and RPS6KB2) and EIF4EBP1 (4E-BP1) (PubMed:29236692, PubMed:33157014).
RHEB is also required for localization of the TSC-TBC complex to lysosomal membranes (PubMed:24529379).
In response to starvation, RHEB is inactivated by the TSC-TBC complex, preventing activation of mTORC1 (PubMed:24529379, PubMed:33157014).
Has low intrinsic GTPase activity (PubMed:15340059).
In response to nutrients, growth factors or amino acids, specifically activates the protein kinase activity of MTOR, the catalytic component of the mTORC1 complex: acts by causing a conformational change that allows the alignment of residues in the active site of MTOR, thereby enhancing the phosphorylation of ribosomal protein S6 kinase (RPS6KB1 and RPS6KB2) and EIF4EBP1 (4E-BP1) (PubMed:29236692, PubMed:33157014).
RHEB is also required for localization of the TSC-TBC complex to lysosomal membranes (PubMed:24529379).
In response to starvation, RHEB is inactivated by the TSC-TBC complex, preventing activation of mTORC1 (PubMed:24529379, PubMed:33157014).
Has low intrinsic GTPase activity (PubMed:15340059).
Miscellaneous
The conserved catalytic Gln-64 found in other Ras-like GTPases seems not to be involved in GTP hydrolysis in RHEB.
Catalytic activity
- GTP + H2O = GDP + H+ + phosphateThis reaction proceeds in the forward direction.
Activity regulation
Alternates between an inactive form bound to GDP and an active form bound to GTP (PubMed:12271141, PubMed:12842888, PubMed:12869586, PubMed:12906785, PubMed:15340059, PubMed:22819219, PubMed:24529379).
Inactivated by the TSC-TBC complex via the GTPase activating protein (GAP) domain of TSC2 (PubMed:12271141, PubMed:12842888, PubMed:12869586, PubMed:12906785, PubMed:15340059, PubMed:22819219, PubMed:24529379).
Autoinhibited by Tyr-35, which constrains the active site conformation, restricting the access of the catalytic Asp-65 to the nucleotide-binding pocket (PubMed:22819219).
Specifically inhibited by NR1 (4-bromo-6-(3,4-dichlorophenylthio)-1-(4-(dimethylcarbamoyl)benzyl)-1H-indole-2-carboxylic acid) (PubMed:29416044).
Inactivated by the TSC-TBC complex via the GTPase activating protein (GAP) domain of TSC2 (PubMed:12271141, PubMed:12842888, PubMed:12869586, PubMed:12906785, PubMed:15340059, PubMed:22819219, PubMed:24529379).
Autoinhibited by Tyr-35, which constrains the active site conformation, restricting the access of the catalytic Asp-65 to the nucleotide-binding pocket (PubMed:22819219).
Specifically inhibited by NR1 (4-bromo-6-(3,4-dichlorophenylthio)-1-(4-(dimethylcarbamoyl)benzyl)-1H-indole-2-carboxylic acid) (PubMed:29416044).
Features
Showing features for binding site, site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Binding site | 16 | GDP (UniProtKB | ChEBI) | ||||
Sequence: S | ||||||
Binding site | 16 | GTP (UniProtKB | ChEBI) | ||||
Sequence: S | ||||||
Binding site | 17 | GDP (UniProtKB | ChEBI) | ||||
Sequence: V | ||||||
Binding site | 18 | GDP (UniProtKB | ChEBI) | ||||
Sequence: G | ||||||
Binding site | 18 | GTP (UniProtKB | ChEBI) | ||||
Sequence: G | ||||||
Binding site | 19 | GDP (UniProtKB | ChEBI) | ||||
Sequence: K | ||||||
Binding site | 19 | GTP (UniProtKB | ChEBI) | ||||
Sequence: K | ||||||
Binding site | 20 | GDP (UniProtKB | ChEBI) | ||||
Sequence: S | ||||||
Binding site | 20 | GTP (UniProtKB | ChEBI) | ||||
Sequence: S | ||||||
Binding site | 20 | Mg2+ (UniProtKB | ChEBI) | ||||
Sequence: S | ||||||
Binding site | 21 | GDP (UniProtKB | ChEBI) | ||||
Sequence: S | ||||||
Binding site | 21 | GTP (UniProtKB | ChEBI) | ||||
Sequence: S | ||||||
Binding site | 32 | GDP (UniProtKB | ChEBI) | ||||
Sequence: V | ||||||
Binding site | 32 | GTP (UniProtKB | ChEBI) | ||||
Sequence: V | ||||||
Binding site | 33 | GDP (UniProtKB | ChEBI) | ||||
Sequence: D | ||||||
Binding site | 35 | GTP (UniProtKB | ChEBI) | ||||
Sequence: Y | ||||||
Site | 35 | Important for autoinhibition of GTPase activity | ||||
Sequence: Y | ||||||
Binding site | 38 | GTP (UniProtKB | ChEBI) | ||||
Sequence: T | ||||||
Binding site | 38 | Mg2+ (UniProtKB | ChEBI) | ||||
Sequence: T | ||||||
Binding site | 119 | GDP (UniProtKB | ChEBI) | ||||
Sequence: N | ||||||
Binding site | 119 | GTP (UniProtKB | ChEBI) | ||||
Sequence: N | ||||||
Binding site | 122 | GDP (UniProtKB | ChEBI) | ||||
Sequence: D | ||||||
Binding site | 122 | GTP (UniProtKB | ChEBI) | ||||
Sequence: D | ||||||
Binding site | 150 | GDP (UniProtKB | ChEBI) | ||||
Sequence: A | ||||||
Binding site | 150 | GTP (UniProtKB | ChEBI) | ||||
Sequence: A |
GO annotations
Keywords
- Molecular function
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameGTP-binding protein Rheb
- EC number
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionQ15382
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Endomembrane system ; Lipid-anchor
Lysosome membrane ; Lipid-anchor
Golgi apparatus membrane ; Lipid-anchor
Endoplasmic reticulum membrane ; Lipid-anchor
Note: Farnesylation is required for recruitment to lysosomal membranes, where it activates the mTORC1 complex.
Keywords
- Cellular component
Disease & Variants
Features
Showing features for mutagenesis, natural variant.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 8 | Decreased ubiquitination by RNF152. Does not affect polyubiquitination in response to amino acids. | ||||
Sequence: K → R | ||||||
Mutagenesis | 15 | Partially resistant to inactivation by TSC1-TSC2. | ||||
Sequence: R → G | ||||||
Mutagenesis | 20 | Deficient in guanine nucleotide binding. Unable to rescue RPS6KB1 from inactivation by amino-acid withdrawal. | ||||
Sequence: S → N | ||||||
Mutagenesis | 35 | Increased GTPase ativity; insensitive to TSC2 regulation, leading to impaired regulation of mTORC1 signaling. | ||||
Sequence: Y → A | ||||||
Mutagenesis | 35 | Dominant mutant, which can activate mTORC1 in both GDP- and GTP-bound forms. | ||||
Sequence: Y → N | ||||||
Mutagenesis | 38 | Slightly impairs signaling through mTORC1, but still binds guanine nucleotides normally. | ||||
Sequence: T → M | ||||||
Mutagenesis | 39 | Impairs RPS6KB1 activation, but still binds guanine nucleotides normally. | ||||
Sequence: I → K | ||||||
Mutagenesis | 40 | No effect. | ||||
Sequence: E → G | ||||||
Mutagenesis | 41 | Impairs interaction with MTOR. Impairs signaling through mTORC1, but still binds guanine nucleotides normally. | ||||
Sequence: N → A | ||||||
Mutagenesis | 43 | No effect. | ||||
Sequence: F → C | ||||||
Mutagenesis | 46 | Causes slight reduction in RPS6KB1 activation. | ||||
Sequence: L → A | ||||||
Mutagenesis | 48 | Causes slightly reduced phosphorylation of EIF4EBP1. | ||||
Sequence: T → A | ||||||
Mutagenesis | 49 | Causes slightly reduced phosphorylation of EIF4EBP1. | ||||
Sequence: V → A | ||||||
Mutagenesis | 53 | Causes slightly reduced phosphorylation of EIF4EBP1. | ||||
Sequence: E → A | ||||||
Mutagenesis | 54 | Partially deficient in guanine nucleotide binding. Fully impairs EIF4EBP1 phosphorylation and RPS6KB1 activation. | ||||
Sequence: Y → A | ||||||
Mutagenesis | 56 | Partially deficient in guanine nucleotide binding. Fully impairs EIF4EBP1 phosphorylation and RPS6KB1 activation. | ||||
Sequence: L → A | ||||||
Mutagenesis | 60 | Unstable protein, which cannot load GTP. | ||||
Sequence: D → A | ||||||
Mutagenesis | 60 | Deficient in guanine nucleotide binding. Unable to rescue RPS6KB1 from inactivation by amino-acid withdrawal. | ||||
Sequence: D → I | ||||||
Mutagenesis | 60 | Unable to bind Mg2+, preventing nucleotide-binding. | ||||
Sequence: D → K | ||||||
Mutagenesis | 64 | Has a higher basal GTPase level, however, is still sensitive to TSC2 GAP activity. | ||||
Sequence: Q → L | ||||||
Mutagenesis | 65 | Renders RHEB insensitive to TSC2 regulation, leading to impaired regulation of mTORC1 signaling. | ||||
Sequence: D → A, E, or N | ||||||
Mutagenesis | 109 | Decreased ubiquitination in response to amino acids; when associated with R-135, R-151 and R-178. | ||||
Sequence: K → R | ||||||
Mutagenesis | 135 | Decreased ubiquitination in response to amino acids; when associated with R-109, R-151 and R-178. | ||||
Sequence: K → R | ||||||
Natural variant | VAR_036310 | 139 | in a colorectal cancer sample; somatic mutation | |||
Sequence: E → K | ||||||
Mutagenesis | 151 | Decreased ubiquitination in response to amino acids; when associated with R-109, R-135 and R-178. | ||||
Sequence: K → R | ||||||
Mutagenesis | 178 | Decreased ubiquitination in response to amino acids; when associated with R-109, R-135 and R-151. | ||||
Sequence: K → R | ||||||
Mutagenesis | 181 | Reduces the ability to rescue RPS6KB1 from inactivation by amino-acid withdrawal. | ||||
Sequence: C → S |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 116 variants from UniProt as well as other sources including ClinVar and dbSNP.
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for chain, cross-link, modified residue (large scale data), modified residue, lipidation, propeptide.
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Chain | PRO_0000082708 | 1-181 | UniProt | GTP-binding protein Rheb | |||
Sequence: MPQSKSRKIAILGYRSVGKSSLTIQFVEGQFVDSYDPTIENTFTKLITVNGQEYHLQLVDTAGQDEYSIFPQTYSIDINGYILVYSVTSIKSFEVIKVIHGKLLDMVGKVQIPIMLVGNKKDLHMERVISYEEGKALAESWNAAFLESSAKENQTAVDVFRRIILEAEKMDGAASQGKSSC | |||||||
Cross-link | 8 | UniProt | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | |||||||
Modified residue (large scale data) | 16 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 130 | UniProt | Phosphoserine; by MAPKAPK5 | ||||
Sequence: S | |||||||
Modified residue | 181 | UniProt | Cysteine methyl ester | ||||
Sequence: C | |||||||
Lipidation | 181 | UniProt | S-farnesyl cysteine | ||||
Sequence: C | |||||||
Propeptide | PRO_0000281365 | 182-184 | UniProt | Removed in mature form | |||
Sequence: SVM |
Post-translational modification
Farnesylation is important for efficiently activating mTORC1-mediated signaling.
Polyubiquitinated in response to amino acid, promoting its interaction with MTOR and mTORC1 activation (PubMed:33157014).
Deubiquitination by ATXN3 promotes recruitment of the TSC-TBC complex and RHEB inactivation by TSC2 (PubMed:33157014).
Monoubiquitinated at Lys-8 by RNF152, promoting its association with the TSC-TBC complex (PubMed:30514904).
Deubiquitinated at Lys-8 by USP4, promoting mTORC1 activation (PubMed:30514904).
Deubiquitination by ATXN3 promotes recruitment of the TSC-TBC complex and RHEB inactivation by TSC2 (PubMed:33157014).
Monoubiquitinated at Lys-8 by RNF152, promoting its association with the TSC-TBC complex (PubMed:30514904).
Deubiquitinated at Lys-8 by USP4, promoting mTORC1 activation (PubMed:30514904).
Phosphorylation by MAPKAPK5 impairs GTP-binding and inactivation.
Keywords
- PTM
Proteomic databases
PTM databases
Interaction
Subunit
Associates with the mTORC1 complex (MTOR, MLST8 and RPTOR) in a guanyl nucleotide-independent manner (PubMed:15854902, PubMed:16098514, PubMed:24529379).
Interacts with TSC2 (PubMed:15854902, PubMed:22819219, PubMed:24529379).
Interacts (when prenylated) with PDE6D; this promotes release from membranes (PubMed:22002721).
Interacts with TSC2 (PubMed:15854902, PubMed:22819219, PubMed:24529379).
Interacts (when prenylated) with PDE6D; this promotes release from membranes (PubMed:22002721).
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | Q15382 | APPBP2 Q92624 | 3 | EBI-1055287, EBI-743771 | |
BINARY | Q15382 | CASP6 P55212 | 3 | EBI-1055287, EBI-718729 | |
BINARY | Q15382 | CCK P06307 | 3 | EBI-1055287, EBI-6624398 | |
BINARY | Q15382 | FGFR3 P22607 | 3 | EBI-1055287, EBI-348399 | |
BINARY | Q15382 | GRIN2C Q14957 | 3 | EBI-1055287, EBI-8285963 | |
BINARY | Q15382 | HIP1 O00291 | 3 | EBI-1055287, EBI-473886 | |
BINARY | Q15382 | LAMP2 P13473-2 | 4 | EBI-1055287, EBI-21591415 | |
BINARY | Q15382 | MTOR P42345 | 2 | EBI-1055287, EBI-359260 | |
BINARY | Q15382 | PLD1 Q13393 | 2 | EBI-1055287, EBI-2827556 | |
BINARY | Q15382 | PRPF40A O75400-2 | 3 | EBI-1055287, EBI-5280197 | |
BINARY | Q15382 | Q9Y649 | 3 | EBI-1055287, EBI-25900580 | |
BINARY | Q15382 | RAN P62826 | 3 | EBI-1055287, EBI-286642 | |
BINARY | Q15382 | TPT1 P13693 | 2 | EBI-1055287, EBI-1783169 | |
BINARY | Q15382 | UBQLN1 Q9UMX0 | 3 | EBI-1055287, EBI-741480 | |
BINARY | PRO_0000082708 | PDE6D O43924 | 5 | EBI-6860739, EBI-712685 |
Protein-protein interaction databases
Chemistry
Miscellaneous
Structure
Family & Domains
Features
Showing features for motif.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Motif | 35-43 | Effector region | ||||
Sequence: YDPTIENTF |
Sequence similarities
Belongs to the small GTPase superfamily. Rheb family.
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Sequence processingThe displayed sequence is further processed into a mature form.
- Length184
- Mass (Da)20,497
- Last updated1996-11-01 v1
- Checksum8F4C8080BDF928FD
Computationally mapped potential isoform sequences
There are 3 potential isoforms mapped to this entry
Features
Showing features for sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Sequence conflict | 118 | in Ref. 2; BAA11211 | ||||
Sequence: G → W |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
Z29677 EMBL· GenBank· DDBJ | CAA82774.1 EMBL· GenBank· DDBJ | mRNA | ||
D78132 EMBL· GenBank· DDBJ | BAA11211.1 EMBL· GenBank· DDBJ | mRNA | ||
AF148645 EMBL· GenBank· DDBJ | AAF73125.1 EMBL· GenBank· DDBJ | mRNA | ||
AF493921 EMBL· GenBank· DDBJ | AAM12635.1 EMBL· GenBank· DDBJ | mRNA | ||
AK125446 EMBL· GenBank· DDBJ | BAG54198.1 EMBL· GenBank· DDBJ | mRNA | ||
BT006958 EMBL· GenBank· DDBJ | AAP35604.1 EMBL· GenBank· DDBJ | mRNA | ||
AC005996 EMBL· GenBank· DDBJ | AAD15548.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
CH471173 EMBL· GenBank· DDBJ | EAW53989.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC016155 EMBL· GenBank· DDBJ | AAH16155.1 EMBL· GenBank· DDBJ | mRNA | ||
BC107705 EMBL· GenBank· DDBJ | AAI07706.1 EMBL· GenBank· DDBJ | mRNA |