P49789 (FHIT_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Bis(5'-adenosyl)-triphosphatase
EC=3.6.1.29

Alternative name(s):
AP3A hydrolase
Short name=AP3Aase
Diadenosine 5',5'''-P1,P3-triphosphate hydrolase
Dinucleosidetriphosphatase
Fragile histidine triad protein

Gene names

Name:

FHIT

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	147 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	Cleaves A-5'-PPP-5'A to yield AMP and ADP. Possible tumor suppressor for specific tissues. Ref.5
Catalytic activity	P(1)-P(3)-bis(5'-adenosyl) triphosphate + H2O = ADP + AMP. Ref.5 Ref.7
Cofactor	Divalent cations. Magnesium, but manganese and to a lesser extent calcium or cobalt can be substituted; but not zinc, cadmium or nickel. Ref.5
Subunit structure	Homodimer. Ref.8
Subcellular location	Cytoplasm Ref.8.
Tissue specificity	Low levels expressed in all tissues tested. Phospho-FHIT observed in liver and kidney, but not in brain and lung. Phospho-FHIT undetected in all tested human tumor cell lines.
Involvement in disease	Note=A chromosomal aberration involving FHIT has been found in a lymphoblastoid cell line established from a family with renal cell carcinoma and thyroid carcinoma. Translocation t(3;8)(p14.2;q24.1) with RNF139. Although the 3p14.2 breakpoint has been shown to interrupt FHIT in its 5-prime non-coding region, it is unlikely that FHIT is causally related to renal or other malignancies. Ref.8 Note=Associated with digestive tract cancers. Numerous tumor types are found to have aberrant forms of FHIT protein due to deletions in a coding region of chromosome 3p14.2 including the fragile site locus FRA3B. Ref.8
Sequence similarities	Contains 1 HIT domain.
Mass spectrometry	Molecular mass is 16733 Da from positions 2 - 147. Determined by MALDI. Ref.8

Ontologies

Keywords
Cellular component	Cytoplasm
Coding sequence diversity	Chromosomal rearrangement
Disease	Tumor suppressor
Ligand	Magnesium Manganese
Molecular function	Hydrolase
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	nucleotide metabolic process Traceable author statement. Source: ProtInc
Molecular function	bis(5'-adenosyl)-triphosphatase activity Inferred from direct assay Ref.5. Source: UniProtKB protein binding Inferred from physical interaction. Source: IntAct
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
FDXR	P22570	4	EBI-741760,EBI-1751533
HSPD1	P10809	5	EBI-741760,EBI-352528
HSPE1	P61604	4	EBI-741760,EBI-711483

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed

Chain

2 – 147

146

Bis(5'-adenosyl)-triphosphatase

PRO_0000109789

Regions

Domain

2 – 109

108

HIT

Region

82 – 99

18

Binding to substrate; phosphate linker

Motif

94 – 98

5

Histidine triad motif

Sites

Active site

96

1

Tele-AMP-histidine intermediate

Binding site

27

1

Substrate

Amino acid modifications

Modified residue

114

1

Phosphotyrosine; by SRC Ref.8

Modified residue

145

1

Phosphotyrosine Ref.8

Experimental info

Mutagenesis

35

1

H → N: 50% decrease in catalytic activity. No loss in substrate binding. Ref.5

Mutagenesis

94

1

H → N: 75% decrease in catalytic activity. No loss in substrate binding. Ref.5

Mutagenesis

96

1

H → G: Total loss of catalytic activity. Rescuable with free imidazole. Ref.5 Ref.7

Mutagenesis

96

1

H → N: Total loss of catalytic activity. No loss in substrate binding. Ref.5 Ref.7

Mutagenesis

98

1

H → N: 99% decrease in catalytic activity. No loss in substrate binding. Ref.5

Mutagenesis

114

1

Y → F: Loss of phosphorylation by SRC. Ref.8

Mutagenesis

145

1

Y → F: No affect on phosphorylation by SRC. Ref.8

Secondary structure

1

.

.

.

.

.

.

.

.

.

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.

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147

Helix Strand Turn

Details...

Beta strand

3 – 5

3

Beta strand

8 – 10

3

Helix

12 – 14

3

Beta strand

15 – 18

4

Beta strand

20 – 26

7

Beta strand

36 – 42

7

Helix

47 – 49

3

Helix

52 – 72

21

Beta strand

76 – 85

10

Helix

86 – 88

3

Beta strand

92 – 94

3

Beta strand

97 – 102

6

Helix

132 – 144

13

Sequences

	Sequence		Length	Mass (Da)
	P49789 [UniParc]. Last modified January 23, 2007. Version 3. Checksum: 14D85961A19ECF3E	FASTA	147	16,858
	10 20 30 40 50 60 MSFRFGQHLI KPSVVFLKTE LSFALVNRKP VVPGHVLVCP LRPVERFHDL RPDEVADLFQ 70 80 90 100 110 120 TTQRVGTVVE KHFHGTSLTF SMQDGPEAGQ TVKHVHVHVL PRKAGDFHRN DSIYEELQKH 130 140 DKEDFPASWR SEEEMAAEAA ALRVYFQ

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers." Ohta M., Inoue H., Cotticelli M.G., Kastury K., Baffa R., Palazzo J., Siprashvili Z., Mori M., McCue P., Druck T., Croce C.M., Huebner K. Cell 84:587-597(1996) [PubMed: 8598045] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
[2]	"Structure and expression of the human FHIT gene in normal and tumor cells." Druck T., Hadaczek P., Fu T.B., Ohta M., Siprashvili Z., Baffa R., Negrini M., Kastury K., Veronese M.L., Rosen D., Rothstein J., McCue P., Cotticelli M.G., Inoue H., Croce C.M., Huebner K. Cancer Res. 57:504-512(1997) [PubMed: 9012482] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"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: Colon.
[4]	Naqvi R.A., Malik A., Anand R., Pasha S.T., Shukla N.K., Husain S.A. Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 94-116.
[5]	"Fhit, a putative tumor suppressor in humans, is a dinucleoside 5',5''-P1,P3-triphosphate hydrolase." Barnes L.D., Garrison P.N., Siprashvili Z., Guranowski A., Robinson A.K., Ingram S.W., Croce C.M., Ohta M., Huebner K. Biochemistry 35:11529-11535(1996) [PubMed: 8794732] [Abstract] Cited for: FUNCTION, CATALYTIC ACTIVITY, COFACTOR, MUTAGENESIS OF HIS-35; HIS-94; HIS-96 AND HIS-98.
[6]	"The hereditary renal cell carcinoma 3;8 translocation fuses FHIT to a patched-related gene, TRC8." Gemmill R.M., West J.D., Boldog F., Tanaka N., Robinson L.J., Smith D.I., Li F., Drabkin H.A. Proc. Natl. Acad. Sci. U.S.A. 95:9572-9577(1998) [PubMed: 9689122] [Abstract] Cited for: CHROMOSOMAL TRANSLOCATION WITH RNF139.
[7]	"The mechanism of action of the fragile histidine triad, Fhit: isolation of a covalent adenylyl enzyme and chemical rescue of H96G-Fhit." Huang K., Arabshahi A., Wei Y., Frey P.A. Biochemistry 43:7637-7642(2004) [PubMed: 15182206] [Abstract] Cited for: CATALYTIC ACTIVITY, MUTAGENESIS OF HIS-96.
[8]	"Fhit is a physiological target of the protein kinase Src." Pekarsky Y., Garrison P.N., Palamarchuk A., Zanesi N., Aqeilan R.I., Huebner K., Barnes L.D., Croce C.M. Proc. Natl. Acad. Sci. U.S.A. 101:3775-3779(2004) [PubMed: 15007172] [Abstract] Cited for: PHOSPHORYLATION BY C-SRC, SUBUNIT, SUBCELLULAR LOCATION, MASS SPECTROMETRY, DISEASE, PHOSPHORYLATION AT TYR-114 AND TYR-145, MUTAGENESIS OF TYR-114 AND TYR-145.
[9]	"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].
[10]	"MAD analysis of FHIT, a putative human tumor suppressor from the HIT protein family." Lima C.D., D'Amico K.L., Naday I., Rosenbaum G., Westbrook E.M., Hendrickson W.A. Structure 5:763-774(1997) [PubMed: 9261067] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS).
[11]	"Structure-based analysis of catalysis and substrate definition in the HIT protein family." Lima C.D., Klein M.G., Hendrickson W.A. Science 278:286-290(1997) [PubMed: 9323207] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS).
[12]	"Genetic, biochemical, and crystallographic characterization of Fhit-substrate complexes as the active signaling form of Fhit." Pace H.C., Garrison P.N., Robinson A.K., Barnes L.D., Draganescu A., Roesler A., Blackburn G.M., Siprashvili Z., Croce C.M., Huebner K., Brenner C. Proc. Natl. Acad. Sci. U.S.A. 95:5484-5489(1998) [PubMed: 9576908] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS).
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U46922 mRNA. Translation: AAA99013.1.
U76271 , U76267, U76268, U76269, U76270 Genomic DNA. Translation: AAB52539.1.
BC032336 mRNA. Translation: AAH32336.1.
AY625256 Genomic DNA. Translation: AAT37530.1.

IPI

IPI00028095.

PIR

A58802.

RefSeq

NP_001159715.1. NM_001166243.1.
NP_002003.1. NM_002012.2.

UniGene

Hs.655995.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1FHI	X-ray	3.10	A	1-147	[»]
1FIT	X-ray	1.85	A	1-147	[»]
2FHI	X-ray	2.60	A	1-147	[»]
2FIT	X-ray	1.90	A	1-147	[»]
3FIT	X-ray	2.40	A	1-147	[»]
4FIT	X-ray	2.50	A	1-147	[»]
5FIT	X-ray	2.30	A	1-147	[»]
6FIT	X-ray	2.60	A	1-147	[»]

ProteinModelPortal

P49789.

SMR

P49789. Positions 2-147.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-29947N.

IntAct

P49789. 10 interactions.

MINT

MINT-150697.

STRING

P49789.

PTM databases

PhosphoSite

P49789.

Polymorphism databases

DMDM

1706794.

Proteomic databases

PeptideAtlas

P49789.

PRIDE

P49789.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000341848; ENSP00000342087; ENSG00000189283.
ENST00000468189; ENSP00000417480; ENSG00000189283.
ENST00000476844; ENSP00000417557; ENSG00000189283.
ENST00000492590; ENSP00000418582; ENSG00000189283.

GeneID

2272.

KEGG

hsa:2272.

UCSC

uc003dkx.2. human.

Organism-specific databases

CTD

2272.

GeneCards

GC03M059712.

H-InvDB

HIX0020704.

HGNC

HGNC:3701. FHIT.

HPA

CAB002684.
HPA018840.
HPA018909.

MIM

601153. gene.

neXtProt

NX_P49789.

Orphanet

151. Familial renal cell carcinoma.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

HBG396802.

HOVERGEN

HBG051614.

InParanoid

P49789.

OMA

TLAIQDG.

OrthoDB

EOG4GQQ68.

PhylomeDB

P49789.

Gene expression databases

ArrayExpress

P49789.

Bgee

P49789.

CleanEx

HS_FHIT.

Genevestigator

P49789.

Family and domain databases

InterPro

IPR011146. His_triad-like_motif.
IPR011151. His_triad_motif.
IPR019808. Histidine_triad_CS.
IPR001310. Histidine_triad_HIT.
[Graphical view]

Gene3D

G3DSA:3.30.428.10. His_triad_motif. 1 hit.

KO

K01522.

PANTHER

PTHR23089. HIT. 1 hit.

Pfam

PF01230. HIT. 1 hit.
[Graphical view]

SUPFAM

SSF54197. His_triad-like_motif. 1 hit.

PROSITE

PS00892. HIT_1. 1 hit.
PS51084. HIT_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

NextBio

9239.

SOURCE

Search...

Entry information

Entry name

FHIT_HUMAN

Accession

Primary (citable) accession number: P49789
Secondary accession number(s): Q6IU12

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	January 23, 2007
Last modified:	December 14, 2011
This is version 115 of the entry and version 3 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.