Reviewed, UniProtKB/Swiss-Prot P49789 (FHIT_HUMAN)

Names and origin

Protein names

Recommended name:
    Bis(5'-adenosyl)-triphosphatase
    EC=3.6.1.29
Alternative name(s):
    Diadenosine 5',5'''-P1,P3-triphosphate hydrolase
    Dinucleosidetriphosphatase
    AP3A hydrolase
      Short name=AP3Aase
    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.6
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.7
Subcellular location	Cytoplasm. Ref.7
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	A chromosomal aberration involving FHIT is observed in early onset bilateral and multifocal clear cell renal carcinoma [MIM:144700]. Translocation t(3;8) (3p14.2). Ref.7 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.7
Sequence similarities	Contains 1 HIT domain.
Mass spectrometry	Molecular mass is 16733 Da from positions 2 - 147. Determined by MALDI. Ref.7

Ontologies

Keywords
Biological process	Cell cycle
Cellular component	Cytoplasm
Coding sequence diversity	Chromosomal rearrangement
Ligand	Magnesium Manganese
Molecular function	Anti-oncogene Hydrolase
PTM	Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	cell cycle Inferred from electronic annotation. Source: UniProtKB-KW negative regulation of cell cycle Inferred from electronic annotation. Source: UniProtKB-KW nucleotide metabolic process Ref.5 Traceable author statement. Source: ProtInc
Cellular component	cytoplasm Ref.7 Inferred from direct assay. Source: UniProtKB
Molecular function	bis(5'-adenosyl)-triphosphatase activity Ref.5 Inferred from direct assay. Source: UniProtKB magnesium ion binding Inferred from electronic annotation. Source: UniProtKB-KW manganese ion binding Inferred from electronic annotation. Source: UniProtKB-KW protein binding Inferred from physical interaction. Source: IntAct
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
FDXR	P22570	3	EBI-741760,EBI-1751533
HSPD1	P10809	2	EBI-741760,EBI-352528
HSPE1	P61604	3	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.7

Modified residue

145

1

Phosphotyrosine Ref.7

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.6

Mutagenesis

96

1

H → N: Total loss of catalytic activity. No loss in substrate binding. Ref.5 Ref.6

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.7

Mutagenesis

145

1

Y → F: No affect on phosphorylation by SRC. Ref.7

Secondary structure

1

.

.

.

.

.

.

.

.

.

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.

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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)
	P49789-1 [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 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.
[7]	"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.
[8]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[9]	"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).
[10]	"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).
[11]	"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

EMBLGenBankDDBJ

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_002003.1.

UniGene

Hs.655995

3D structure databases

PDBPDBe

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	[»]

ModBase

Search...

Protein-protein interaction databases

IntAct

P49789. 7 interactions.

PTM databases

PhosphoSite

P49789.

Proteomic databases

PeptideAtlas

P49789.

PRIDE

P49789.

Genome annotation databases

Ensembl

ENSG00000189283. Homo sapiens. [Contig view]

GeneID

2272.

KEGG

hsa:2272.

Organism-specific databases

GeneCards

GC03M059712.

H-InvDB

HIX0020704.

HGNC

HGNC:3701. FHIT.

HPA

CAB002684.
HPA018840.
HPA018909.

MIM

144700. phenotype.
601153. gene.

Orphanet

151. Renal cell carcinoma, familial.

PharmGKB

PA28140.

GenAtlas

Search...

Phylogenomic databases

HOVERGEN

P49789.

OMA

P49789. HILPRKA.

Enzyme and pathway databases

BRENDA

3.6.1.29. 247.

Gene expression databases

ArrayExpress

P49789.

Bgee

P49789.

CleanEx

HS_FHIT.

Family and domain databases

InterPro

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.

PANTHER

PTHR23089. HIT. 1 hit.

Pfam

PF01230. HIT. 1 hit.
[Graphical view]

PROSITE

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

ProtoNet

Search...

Other Resources

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:	June 16, 2009
This is version 89 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)