Reviewed, UniProtKB/Swiss-Prot P01112 (RASH_HUMAN)

Names and origin

Protein names

Recommended name:
    GTPase HRas
Alternative name(s):
    Transforming protein p21
    p21ras
    H-Ras-1
    c-H-ras
    Ha-Ras

Gene names

Name:	HRAS
Synonyms:	HRAS1

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	189 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	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
Enzyme regulation	Alternate between an inactive form bound to GDP and an active form bound to GTP. Activated by a guanine nucleotide-exchange factor (GEF) and inactivated by a GTPase-activating protein (GAP).
Subunit structure	In its GTP-bound form interacts with PLCE1. Interacts with TBC1D10C. Interacts with RGL3 By similarity. Forms a signaling complex with RASGRP1 and DGKZ. Interacts with RASSF5.
Subcellular location	Cell membrane; Lipid-anchor; Cytoplasmic side. Golgi apparatus membrane; Lipid-anchor. Note= Shuttles between the plasma membrane and the Golgi apparatus.
Post-translational modification	Palmitoylated by the ZDHHC9-GOLGA7 complex. A continuous cycle of de- and re-palmitoylation regulates rapid exchange between plasma membrane and Golgi. S-nitrosylated; critical for redox regulation. Important for stimulating guanine nucleotide exchange. No structural perturbation on nitrosylation.
Involvement in disease	Defects in HRAS are the cause of Costello syndrome [MIM:218040]; also known as faciocutaneoskeletal syndrome. Costello syndrome is a rare condition characterized by prenatally increased growth, postnatal growth deficiency, mental retardation, distinctive facial appearance, cardiovascular abnormalities (typically pulmonic stenosis, hypertrophic cardiomyopathy and/or atrial tachycardia), tumor predisposition, skin and musculoskeletal abnormalities. Defects in HRAS are the cause of congenital myopathy with excess of muscle spindles (CMEMS) [MIM:218040]. CMEMS is a variant of Costello syndrome. Defects in HRAS may be a cause of susceptibility to Hurthle cell thyroid carcinoma [MIM:607464]; also known as Hurthle cell thyroid neoplasia. Hurthle cell thyroid carcinoma accounts for approximately 3% of all thyroid cancers. Although they are classified as variants of follicular neoplasms, they are more often multifocal and somewhat more aggressive and are less likely to take up iodine than are other follicular neoplasms. Mutations which change positions 12, 13 or 61 activate the potential of c-ras to transform cultured cells and are implicated in a variety of human tumors. Defects in HRAS are a cause of bladder cancer [MIM:109800]. Defects in HRAS are the cause of oral squamous cell carcinoma (OSCC).
Sequence similarities	Belongs to the small GTPase superfamily. Ras family.
Mass spectrometry	Molecular weight is 6.223±2 Da from positions 112 - 166. Determined by ESI. Ref.18 Molecular weight is 6.253±2 Da from positions 112 - 166. Determined by ESI. Includes one nitric oxide molecule. Ref.18

Ontologies

Keywords
Cellular component	Cell membrane Golgi apparatus Membrane
Disease	Disease mutation Proto-oncogene
Ligand	GTP-binding Nucleotide-binding
PTM	Acetylation Lipoprotein Methylation Palmitate Prenylation S-nitrosylation
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	cell surface receptor linked signal transduction Traceable author statement. Source: ProtInc chemotaxis Traceable author statement. Source: ProtInc organ morphogenesis Traceable author statement. Source: ProtInc
Cellular component	Golgi membrane Inferred from electronic annotation. Source: UniProtKB-SubCell plasma membrane Traceable author statement. Source: ProtInc
Molecular function	GTP binding Inferred from electronic annotation. Source: InterPro protein C-terminus binding Ref.29 Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
BRAP	Q7Z569	3	EBI-350145,EBI-349900
byr2	P28829	1	EBI-350145,EBI-1032333	From a different organism.
Pik3ca	P42337	1	EBI-350145,EBI-641748	From a different organism.
PIK3CG	P48736	1	EBI-350145,EBI-1030384
Rabac1	Q9Z0S9	2	EBI-350145,EBI-476965	From a different organism.
RAF1	P04049	5	EBI-350145,EBI-365996
Rapgef4	Q9EQZ6	2	EBI-350145,EBI-772212	From a different organism.
RASA1	P20936	1	EBI-350145,EBI-1026476
RASSF1	Q9NS23-2	2	EBI-350145,EBI-438698
RASSF5	Q8WWW0	1	EBI-350145,EBI-367390
Rassf5	Q5EBH1-2	2	EBI-350145,EBI-960547	From a different organism.
RGL1	Q9NZL6	1	EBI-350145,EBI-365926
RIN1	Q13671	2	EBI-350145,EBI-366017
RIN1	Q13671-1	1	EBI-350145,EBI-366030
SOS1	Q07889	1	EBI-350145,EBI-297487

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 186

186

GTPase HRas

PRO_0000042996

Initiator methionine

1

1

Removed; alternate

Chain

2 – 186

185

GTPase HRas

PRO_0000326476

Propeptide

187 – 189

3

Removed in mature form

PRO_0000042997

Regions

Nucleotide binding

10 – 17

8

GTP

Nucleotide binding

57 – 61

5

GTP

Nucleotide binding

116 – 119

4

GTP

Region

166 – 185

20

Hypervariable region

Motif

32 – 40

9

Effector region

Amino acid modifications

Modified residue

1

1

N-acetylmethionine; alternate

Modified residue

2

1

N-acetylthreonine

Modified residue

118

1

S-nitrosocysteine

Modified residue

186

1

Cysteine methyl ester

Lipidation

181

1

S-palmitoyl cysteine

Lipidation

184

1

S-palmitoyl cysteine

Lipidation

186

1

S-farnesyl cysteine

Natural variations

Natural variant

12

1

G → A in Costello syndrome.

VAR_026106

Natural variant

12

1

G → C in Costello syndrome.

VAR_045975

Natural variant

12

1

G → E in Costello syndrome.

VAR_045976

Natural variant

12

1

G → S in Costello syndrome, OSCC and CMEMS.

VAR_006837

Natural variant

12

1

G → V in Costello syndrome, bladder carcinoma and CMEMS; constitutively activated; interacts and recruits PLCE1 to plasma membrane; loss of interaction with and recruitment to plasma membrane of PLCE1 when associated with F-32; loss of interaction with PLCE1 when associated with G-26, F-32 and S-35; no effect on interaction with PLCE1 when associated with A-29, G-34, G-37, N-38 and C-39.

VAR_006836

Natural variant

13

1

G → C in Costello syndrome.

VAR_026107

Natural variant

13

1

G → D in Costello syndrome.

VAR_026108

Natural variant

22

1

Q → K in CMEMS.

VAR_045977

Natural variant

58

1

T → I in Costello syndrome.

VAR_045978

Natural variant

61

1

Q → K in follicular thyroid carcinoma samples; somatic mutation; increases transformation of cultured cell lines.

VAR_045979

Natural variant

61

1

Q → L in melanoma; strongly reduced GTP hydrolysis in the presence of RAF1; increases transformation of cultured cell lines.

VAR_006838

Natural variant

63

1

E → K in CMEMS.

VAR_045980

Natural variant

117

1

K → R in Costello syndrome.

VAR_045981

Natural variant

146

1

A → T in Costello syndrome.

VAR_045982

Natural variant

146

1

A → V in Costello syndrome.

VAR_045983

Experimental info

Mutagenesis

17

1

S → N: Dominant negative. Prevents PLCE1 EGF-induced recruitment to plasma membrane

Mutagenesis

26

1

N → G: Loss of interaction with PLCE1; when associated with V-12

Mutagenesis

29

1

V → A: No effect on interaction with PLCE1; when associated with V-12

Mutagenesis

32

1

Y → F: Loss of interaction and recruitment to plasma membrane of PLCE1; when associated with V-12

Mutagenesis

34

1

P → G: No effect on interaction with PLCE1; when associated with V-12

Mutagenesis

35

1

T → S: Loss of interaction with PLCE1; when associated with V-12

Mutagenesis

37

1

E → G: No effect on interaction with PLCE1; when associated with V-12

Mutagenesis

38

1

D → N: No effect on interaction with PLCE1; when associated with V-12

Mutagenesis

39

1

S → C: No effect on interaction with PLCE1; when associated with V-12

Mutagenesis

59

1

A → T: Loss of GTPase activity and creation of an autophosphorylation site

Mutagenesis

61

1

Q → I: Moderately increased transformation of cultured cell lines

Mutagenesis

61

1

Q → V: Strongly increased transformation of cultured cell lines

Mutagenesis

83

1

A → T: GTP-binding activity reduced by factor of 30

Mutagenesis

118

1

C → S: Abolishes S-nitrosylation. No stimulation of guanine nucleotide exchange

Mutagenesis

119

1

D → N: Loss of GTP-binding activity

Mutagenesis

144

1

T → I: GTP-binding activity reduced by factor of 25

Mutagenesis

164 – 165

2

RQ → AV: Loss of GTP-binding activity

Mutagenesis

181

1

C → S: Exclusively localized in Golgi. Non-specifically localized on all endomembranes; when associated with S-184

Mutagenesis

184

1

C → S: Mainly localized in Golgi. Non-specifically localized on all endomembranes; when associated with S-181

Secondary structure

1

.

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189

Helix Strand Turn

Details...

Beta strand

2 – 11

10

Helix

16 – 25

10

Beta strand

36 – 46

11

Beta strand

49 – 58

10

Helix

62 – 64

3

Helix

65 – 74

10

Beta strand

76 – 83

8

Helix

87 – 91

5

Helix

93 – 104

12

Beta strand

111 – 116

6

Helix

127 – 137

11

Beta strand

141 – 143

3

Turn

146 – 148

3

Helix

152 – 164

13

Sequences

	Sequence		Length	Mass (Da)
	P01112-1 [UniParc]. Last modified July 21, 1986. Version 1. Checksum: EE6DC2D933E2856A	FASTA	189	21,298
	10 20 30 40 50 60 MTEYKLVVVG AGGVGKSALT IQLIQNHFVD EYDPTIEDSY RKQVVIDGET CLLDILDTAG 70 80 90 100 110 120 QEEYSAMRDQ YMRTGEGFLC VFAINNTKSF EDIHQYREQI KRVKDSDDVP MVLVGNKCDL 130 140 150 160 170 180 AARTVESRQA QDLARSYGIP YIETSAKTRQ GVEDAFYTLV REIRQHKLRK LNPPDESGPG CMSCKCVLS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Complete nucleotide sequences of the T24 human bladder carcinoma oncogene and its normal homologue." Capon D.J., Chen E.Y., Levinson A.D., Seeburg P.H., Goeddel D.V. Nature 302:33-37(1983) [PubMed: 6298635] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[2]	"Nucleotide sequence analysis of the T24 human bladder carcinoma oncogene." Reddy E.P. Science 220:1061-1063(1983) [PubMed: 6844927] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"Molecular cloning and the total nucleotide sequence of the human c-Ha-ras-1 gene activated in a melanoma from a Japanese patient." Sekiya T., Fushimi M., Hori H., Hirohashi S., Nishimura S., Sugimura T. Proc. Natl. Acad. Sci. U.S.A. 81:4771-4775(1984) [PubMed: 6087347] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[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]	"Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)." Halleck A., Ebert L., Mkoundinya M., Schick M., Eisenstein S., Neubert P., Kstrang K., Schatten R., Shen B., Henze S., Mar W., Korn B., Zuo D., Hu Y., LaBaer J. Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[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 (OCT-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[7]	"Human protein factory: an infrastructure to convert the human transcriptome into the in vitro-expressed human proteome of versatile utility." Goshima N., Kawamura Y., Fukumoto A., Miura A., Honma R., Satoh R., Wakamatsu A., Yamamoto J., Kimura K., Nishikawa T., Andoh T., Iida Y., Ishikawa K., Ito E., Kagawa N., Kaminaga C., Kanehori K., Kawakami B. , Kenmochi K., Kimura R., Kobayashi M., Kuroita T., Kuwayama H., Maruyama Y., Matsuo K., Minami K., Mitsubori M., Mori M., Morishita R., Murase A., Nishikawa A., Nishikawa S., Okamoto T., Sakagami N., Sakamoto Y., Sasaki Y., Seki T., Sono S., Sugiyama A., Sumiya T., Takayama T., Takayama Y., Takeda H., Togashi T., Yahata K., Yamada H., Yanagisawa Y., Endo Y., Imamoto F., Kisu Y., Tanaka S., Isogai T., Imai J., Watanabe S., Nomura N. Submitted (JUL-2008) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[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 (JUL-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].
[10]	Bienvenut W.V., Calvo F.