Q15382 (RHEB_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
GTP-binding protein Rheb

Alternative name(s):
Ras homolog enriched in brain

Gene names

Name:	RHEB
Synonyms:	RHEB2

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	184 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Stimulates the phosphorylation of S6K1 and EIF4EBP1 through activation of mTORC1 signaling. Activates the protein kinase activity of mTORC1. Has low intrinsic GTPase activity. Ref.10 Ref.11 Ref.12 Ref.14 Ref.15 Ref.16
Enzyme regulation	Alternates between an inactive form bound to GDP and an active form bound to GTP. Inactivated by TSC1-TSC2 via the GTPase activating protein (GAP) domain of TSC2.
Subunit structure	Binds to mTORC1 in a guanyl nucleotide-independent manner. Interacts directly with MTOR, MLST8 and RPTOR. Interacts with TSC2. Ref.14 Ref.15
Subcellular location	Cell membrane; Lipid-anchor; Cytoplasmic side Potential.
Tissue specificity	Ubiquitous. Highest levels observed in skeletal and cardiac muscle.
Post-translational modification	Farnesylation is important for efficiently activating mTORC1-mediated signaling. Phosphorylation by MAPKAPK5 impairs GTP-binding and inactivation By similarity.
Miscellaneous	The conserved catalytic Gln-64 found in other Ras-like GTPases seems not to be involved in GTP hydrolysis in RHEB.
Sequence similarities	Belongs to the small GTPase superfamily. Rheb family.

Ontologies

Keywords
Cellular component	Cell membrane Membrane
Coding sequence diversity	Polymorphism
Ligand	GTP-binding Magnesium Metal-binding Nucleotide-binding
PTM	Lipoprotein Methylation Phosphoprotein Prenylation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	cell cycle arrest Traceable author statement. Source: Reactome insulin receptor signaling pathway Traceable author statement. Source: Reactome positive regulation of TOR signaling cascade Inferred from mutant phenotype Ref.16. Source: UniProtKB small GTPase mediated signal transduction Inferred from electronic annotation. Source: InterPro
Cellular component	cytosol Traceable author statement. Source: Reactome plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	GTP binding Traceable author statement. Source: ProtInc GTPase activity Traceable author statement. Source: ProtInc metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 181

181

GTP-binding protein Rheb

PRO_0000082708

Propeptide

182 – 184

3

Removed in mature form

PRO_0000281365

Regions

Nucleotide binding

16 – 21

6

GTP

Nucleotide binding

32 – 38

7

GTP

Nucleotide binding

119 – 122

4

GTP

Nucleotide binding

149 – 150

2

GTP

Motif

35 – 43

9

Effector region By similarity

Sites

Metal binding

20

1

Magnesium

Metal binding

38

1

Magnesium

Amino acid modifications

Modified residue

130

1

Phosphoserine; by MAPKAPK5 By similarity

Modified residue

181

1

Cysteine methyl ester Probable

Lipidation

181

1

S-farnesyl cysteine Ref.13

Natural variations

Natural variant

139

1

E → K in a colorectal cancer sample; somatic mutation. Ref.19

VAR_036310

Experimental info

Mutagenesis

15

1

R → G: Partially resistant to inactivation by TSC1-TSC2. Ref.12

Mutagenesis

20

1

S → N: Deficient in guanine nucleotide binding. Unable to rescue S6K1 from inactivation by amino-acid withdrawal. Ref.12 Ref.14

Mutagenesis

38

1

T → M: Slightly impairs signaling through mTORC1, but still binds guanine nucleotides normally. Ref.14 Ref.15

Mutagenesis

39

1

I → K: Impairs S6K1 activation, but still binds guanine nucleotides normally. Ref.14

Mutagenesis

40

1

E → G: No effect. Ref.15

Mutagenesis

41

1

N → A: Impairs interaction with MTOR. Impairs signaling through mTORC1, but still binds guanine nucleotides normally. Ref.14 Ref.15

Mutagenesis

43

1

F → C: No effect. Ref.15

Mutagenesis

46

1

L → A: Causes slight reduction in S6K1 activation. Ref.15

Mutagenesis

48

1

T → A: Causes slightly reduced phosphorylation of EIF4EBP1. Ref.15

Mutagenesis

49

1

V → A: Causes slightly reduced phosphorylation of EIF4EBP1. Ref.15

Mutagenesis

53

1

E → A: Causes slightly reduced phosphorylation of EIF4EBP1. Ref.15

Mutagenesis

54

1

Y → A: Partially deficient in guanine nucleotide binding. Fully impairs EIF4EBP1 phosphorylation and S6K1 activation. Ref.15

Mutagenesis

56

1

L → A: Partially deficient in guanine nucleotide binding. Fully impairs EIF4EBP1 phosphorylation and S6K1 activation. Ref.15

Mutagenesis

60

1

D → I: Deficient in guanine nucleotide binding. Unable to rescue S6K1 from inactivation by amino-acid withdrawal. Ref.12

Mutagenesis

64

1

Q → L: Has a higher basal GTPase level, however, is still sensitive to TSC2 GAP activity. Ref.12

Mutagenesis

181

1

C → S: Reduces the ability to rescue S6K1 from inactivation by amino-acid withdrawal. Ref.12

Sequence conflict

118

1

G → W in BAA11211. Ref.2

Secondary structure

1

.

.

.

.

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.

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184

Helix Strand Turn

Details...

Beta strand

5 – 14

10

Helix

19 – 28

10

Beta strand

41 – 49

9

Beta strand

52 – 60

9

Helix

72 – 74

3

Beta strand

80 – 86

7

Helix

90 – 107

18

Beta strand

114 – 119

6

Helix

124 – 126

3

Helix

131 – 141

11

Beta strand

144 – 147

4

Helix

153 – 169

17

Sequences

	Sequence		Length	Mass (Da)
	Q15382 [UniParc]. Last modified November 1, 1996. Version 1. Checksum: 8F4C8080BDF928FD	FASTA	184	20,497
	10 20 30 40 50 60 MPQSKSRKIA ILGYRSVGKS SLTIQFVEGQ FVDSYDPTIE NTFTKLITVN GQEYHLQLVD 70 80 90 100 110 120 TAGQDEYSIF PQTYSIDING YILVYSVTSI KSFEVIKVIH GKLLDMVGKV QIPIMLVGNK 130 140 150 160 170 180 KDLHMERVIS YEEGKALAES WNAAFLESSA KENQTAVDVF RRIILEAEKM DGAASQGKSS CSVM

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"A novel approach for expression cloning of small GTPases: identification, tissue distribution and chromosome mapping of the human homolog of rheb." Gromov P.S., Madsen P., Tomerup N., Celis J.E. FEBS Lett. 377:221-226(1995) [PubMed: 8543055] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Psoriatic skin.
[2]	"Isolation of cDNA and genomic clones of a human Ras-related GTP-binding protein gene and its chromosomal localization to the long arm of chromosome 7, 7q36." Mizuki N., Kimura M., Ohno S., Miyata S., Sato M., Ando H., Ishihara M., Goto K., Watanabe S., Yamazaki M., Ono A., Taguchi S., Okumura K., Nogami M., Taguchi H., Ando A., Inoko H. Genomics 34:114-118(1996) [PubMed: 8661031] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Skin.
[3]	"Detection of membrane-associated proteins using serum of mice immunized with membrane fractions of breast carcinoma cells." Weidenmueller U., Tur M.K., Tawadros S., Engert A., Barth S. Submitted (MAY-1999) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Mammary carcinoma.
[4]	"cDNA clones of human proteins involved in signal transduction sequenced by the Guthrie cDNA resource center (www.cdna.org)." Puhl H.L. III, Ikeda S.R., Aronstam R.S. Submitted (MAR-2002) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Brain.
[5]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Brain.
[6]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[7]	"The DNA sequence of human chromosome 7." Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H., Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A., Delehaunty K.D., Miner T.L. , Nash W.E., Cordes M., Du H., Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C., Latreille P., Miller N., Johnson D., Murray J., Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E., Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H., Wilson R.K. Nature 424:157-164(2003) [PubMed: 12853948] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[8]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[9]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Muscle and Testis.
[10]	"Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling." Tee A.R., Fingar D.C., Manning B.D., Kwiatkowski D.J., Cantley L.C., Blenis J. Proc. Natl. Acad. Sci. U.S.A. 99:13571-13576(2002) [PubMed: 12271141] [Abstract] Cited for: FUNCTION.
[11]	"Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling." Inoki K., Li Y., Xu T., Guan K.-L. Genes Dev. 17:1829-1834(2003) [PubMed: 12869586] [Abstract] Cited for: FUNCTION.
[12]	"Biochemical and functional characterizations of small GTPase Rheb and TSC2 GAP activity." Li Y., Inoki K., Guan K.-L. Mol. Cell. Biol. 24:7965-7975(2004) [PubMed: 15340059] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF ARG-15; SER-20; ASP-60; GLN-64 AND CYS-181.
[13]	"A tagging-via-substrate technology for detection and proteomics of farnesylated proteins." Kho Y., Kim S.C., Jiang C., Barma D., Kwon S.W., Cheng J., Jaunbergs J., Weinbaum C., Tamanoi F., Falck J., Zhao Y. Proc. Natl. Acad. Sci. U.S.A. 101:12479-12484(2004) [PubMed: 15308774] [Abstract] Cited for: ISOPRENYLATION AT CYS-181.
[14]	"Rheb binds and regulates the mTOR kinase." Long X., Lin Y., Ortiz-Vega S., Yonezawa K., Avruch J. Curr. Biol. 15:702-713(2005) [PubMed: 15854902] [Abstract] Cited for: FUNCTION, INTERACTION WITH MTOR; MLST8; RPTOR AND TSC2, MUTAGENESIS OF SER-20; THR-38; ILE-39 AND ASN-41.
[15]	"Analysis of mTOR signaling by the small G-proteins, Rheb and RhebL1." Tee A.R., Blenis J., Proud C.G. FEBS Lett. 579:4763-4768(2005) [PubMed: 16098514] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF THR-38; GLU-40; ASN-41; PHE-43; LEU-46; THR-48; VAL-49; GLU-53; TYR-54 AND LEU-56, INTERACTION WITH MTOR.
[16]	"Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids." Sancak Y., Bar-Peled L., Zoncu R., Markhard A.L., Nada S., Sabatini D.M. Cell 141:290-303(2010) [PubMed: 20381137] [Abstract] Cited for: FUNCTION.
[17]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed: 21269460] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[18]	"Structural basis for the unique biological function of small GTPase RHEB." Yu Y., Li S., Xu X., Li Y., Guan K., Arnold E., Ding J. J. Biol. Chem. 280:17093-17100(2005) [PubMed: 15728574] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 1-169 IN COMPLEX WITH GDP AND GTP.
[19]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E. Science 314:268-274(2006) [PubMed: 16959974] [Abstract] Cited for: VARIANT [LARGE SCALE ANALYSIS] LYS-139.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

Z29677 mRNA. Translation: CAA82774.1.
D78132 mRNA. Translation: BAA11211.1.
AF148645 mRNA. Translation: AAF73125.1.
AF493921 mRNA. Translation: AAM12635.1.
AK125446 mRNA. Translation: BAG54198.1.
BT006958 mRNA. Translation: AAP35604.1.
AC005996 Genomic DNA. Translation: AAD15548.1.
CH471173 Genomic DNA. Translation: EAW53989.1.
BC016155 mRNA. Translation: AAH16155.1.
BC107705 mRNA. Translation: AAI07706.1.

IPI

IPI00016669.

PIR

S41960. S68419.

RefSeq

NP_005605.1. NM_005614.3.

UniGene

Hs.283521.
Hs.568850.
Hs.647068.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1XTQ	X-ray	2.00	A	1-169	[»]
1XTR	X-ray	2.65	A	1-169	[»]
1XTS	X-ray	2.80	A	1-169	[»]
3T5G	X-ray	1.70	A	1-181	[»]

ProteinModelPortal

Q15382.

SMR

Q15382. Positions 6-174.

DisProt

DP00364.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-42816N.

IntAct

Q15382. 9 interactions.

MINT

MINT-1365334.

STRING

Q15382.

PTM databases

PhosphoSite

Q15382.

Polymorphism databases

DMDM

6919957.

Proteomic databases

PRIDE

Q15382.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000262187; ENSP00000262187; ENSG00000106615.

GeneID

6009.

KEGG

hsa:6009.

UCSC

uc003wkh.1. human.

Organism-specific databases

CTD

6009.

GeneCards

GC07M151163.

H-InvDB

HIX0007233.

HGNC

HGNC:10011. RHEB.

HPA

CAB019436.

MIM

601293. gene.

neXtProt

NX_Q15382.

PharmGKB

PA34389.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG11731.

HOGENOM

HBG745225.

HOVERGEN

HBG009351.

InParanoid

Q15382.

OMA

HFVESYY.

OrthoDB

EOG4VMFGG.

PhylomeDB

Q15382.

Enzyme and pathway databases

Pathway_Interaction_DB

pi3kciaktpathway. Class I PI3K signaling events mediated by Akt.
mtor_4pathway. mTOR signaling pathway.

Reactome

REACT_111102. Signal Transduction.

Gene expression databases

ArrayExpress

Q15382.

Bgee

Q15382.

CleanEx

HS_RHEB.

Genevestigator

Q15382.

GermOnline

ENSG00000106615. Homo sapiens.

Family and domain databases

InterPro

IPR005225. Small_GTP-bd_dom.
IPR001806. Small_GTPase.
IPR020849. Small_GTPase_Ras.
[Graphical view]

KO

K07208.

PANTHER

PTHR24070. PTHR24070. 1 hit.

Pfam

PF00071. Ras. 1 hit.
[Graphical view]

PRINTS

PR00449. RASTRNSFRMNG.

SMART

SM00173. RAS. 1 hit.
[Graphical view]

TIGRFAMs

TIGR00231. Small_GTP. 1 hit.

PROSITE

PS51421. RAS. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

NextBio

23445.

SOURCE

Search...

Entry information

Entry name

RHEB_HUMAN

Accession

Primary (citable) accession number: Q15382
Secondary accession number(s): B3KWN6 , D3DX13, Q53Y56, Q99444

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 30, 2000
Last sequence update:	November 1, 1996
Last modified:	January 25, 2012
This is version 132 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.