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) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	147 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Cleaves P(1)-P(3)-bis(5'-adenosyl) triphosphate (Ap3A) to yield AMP and ADP. Can also hydrolyze P(1)-P(4)-bis(5'-adenosyl) tetraphosphate (Ap4A), but has extremely low activity with ATP. Modulates transcriptional activation by CTNNB1 and thereby contributes to regulate the expression of genes essential for cell proliferation and survival, such as CCND1 and BIRC5. Plays a role in the induction of apoptosis via SRC and AKT1 signaling pathways. Inhibits MDM2-mediated proteasomal degradation of p53/TP53 and thereby plays a role in p53/TP53-mediated apoptosis. Induction of apoptosis depends on the ability of FHIT to bind P(1)-P(3)-bis(5'-adenosyl) triphosphate or related compounds, but does not require its catalytic activity. Functions as tumor suppressor. Ref.5 Ref.8 Ref.10 Ref.12 Ref.13 Ref.16
Catalytic activity	P(1)-P(3)-bis(5'-adenosyl) triphosphate + H2O = ADP + AMP. Ref.5 Ref.8 Ref.9 Ref.16 Ref.17
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 Ref.17
Subunit structure	Homodimer. Interacts with UBE2I. Interacts with MDM2. Interacts with CTNNB1. Identified in a complex with CTNNB1 and LEF1. Ref.7 Ref.10 Ref.11 Ref.13 Ref.16 Ref.17
Subcellular location	Cytoplasm Ref.10 Ref.11.
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.
Post-translational modification	Phosphorylation at Tyr-114 by SRC is required for induction of apoptosis.
Involvement in disease	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.11 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.11
Sequence similarities	Contains 1 HIT domain.
Mass spectrometry	Molecular mass is 16733 Da from positions 2 - 147. Determined by MALDI. Ref.11

Ontologies

Keywords
Biological process	Apoptosis Transcription Transcription regulation
Cellular component	Cytoplasm
Coding sequence diversity	Chromosomal rearrangement
Disease	Tumor suppressor
Ligand	Magnesium Manganese Nucleotide-binding
Molecular function	Hydrolase
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	DNA replication Inferred from electronic annotation. Source: Compara intrinsic apoptotic signaling pathway by p53 class mediator Inferred from mutant phenotype Ref.10. Source: UniProtKB negative regulation of proteasomal ubiquitin-dependent protein catabolic process Inferred from mutant phenotype Ref.10. Source: UniProtKB purine nucleotide metabolic process Inferred from direct assay Ref.16. Source: UniProtKB regulation of transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	cytosol Inferred from direct assay Ref.10. Source: UniProtKB intracellular membrane-bounded organelle Inferred from direct assay. Source: HPA
Molecular_function	bis(5'-adenosyl)-triphosphatase activity Inferred from direct assay Ref.5Ref.16. Source: UniProtKB nucleotide binding Inferred from electronic annotation. Source: UniProtKB-KW
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

Chain

1 – 147

147

Bis(5'-adenosyl)-triphosphatase

PRO_0000109789

Regions

Domain

2 – 109

108

HIT

Nucleotide binding

89 – 92

4

Substrate

Motif

94 – 98

5

Histidine triad motif

Sites

Active site

96

1

Tele-AMP-histidine intermediate Ref.9 Ref.16

Binding site

8

1

Substrate

Binding site

27

1

Substrate

Binding site

83

1

Substrate

Binding site

98

1

Substrate

Site

114

1

Important for induction of apoptosis

Amino acid modifications

Modified residue

114

1

Phosphotyrosine; by SRC Ref.11

Modified residue

145

1

Phosphotyrosine Ref.11

Experimental info

Mutagenesis

10

1

I → W: Strongly reduces affinity for substrates and impairs apoptosis; when associated with W-25. Ref.8

Mutagenesis

25

1

L → W: Reduces affinity for substrates and impairs apoptosis. Strongly reduces affinity for substrates and impairs apoptosis; when associated with W-10. Ref.8

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 → D: Loss of catalytic activity. Ref.5 Ref.8 Ref.9 Ref.17

Mutagenesis

96

1

H → G: Total loss of catalytic activity. Rescuable with free imidazole. Ref.5 Ref.8 Ref.9 Ref.17

Mutagenesis

96

1

H → N: Total loss of catalytic activity. No loss in substrate binding. Ref.5 Ref.8 Ref.9 Ref.17

Mutagenesis

98

1

H → N: 98% decrease in catalytic activity. Ref.5

Mutagenesis

114

1

Y → A: Impairs induction of apoptosis. Strongly reduced affinity for substrates. Ref.11 Ref.12

Mutagenesis

114

1

Y → D: Impairs induction of apoptosis. Reduces affinity for substrates. Ref.11 Ref.12

Mutagenesis

114

1

Y → F: Loss of phosphorylation by SRC. Impairs induction of apoptosis. Ref.11 Ref.12

Mutagenesis

145

1

Y → F: No effect on phosphorylation by SRC. Ref.11

Secondary structure

1

.

.

.

.

.

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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 – 82

7

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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [Abstract] Cited for: CHROMOSOMAL TRANSLOCATION WITH RNF139.
[7]	"Association of FHIT (fragile histidine triad), a candidate tumour suppressor gene, with the ubiquitin-conjugating enzyme hUBC9." Shi Y., Zou M., Farid N.R., Paterson M.C. Biochem. J. 352:443-448(2000) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH UBE2I.
[8]	"Designed FHIT alleles establish that Fhit-induced apoptosis in cancer cells is limited by substrate binding." Trapasso F., Krakowiak A., Cesari R., Arkles J., Yendamuri S., Ishii H., Vecchione A., Kuroki T., Bieganowski P., Pace H.C., Huebner K., Croce C.M., Brenner C. Proc. Natl. Acad. Sci. U.S.A. 100:1592-1597(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF ILE-10; LEU-25 AND HIS-96.
[9]	"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] [Europe PMC] [Abstract] Cited for: ACTIVE SITE, CATALYTIC ACTIVITY, MUTAGENESIS OF HIS-96.
[10]	"Synergistic tumor suppression by coexpression of FHIT and p53 coincides with FHIT-mediated MDM2 inactivation and p53 stabilization in human non-small cell lung cancer cells." Nishizaki M., Sasaki J., Fang B., Atkinson E.N., Minna J.D., Roth J.A., Ji L. Cancer Res. 64:5745-5752(2004) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH MDM2.
[11]	"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] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION BY SRC, SUBUNIT, SUBCELLULAR LOCATION, MASS SPECTROMETRY, DISEASE, PHOSPHORYLATION AT TYR-114 AND TYR-145, MUTAGENESIS OF TYR-114 AND TYR-145.
[12]	"Fhit modulation of the Akt-survivin pathway in lung cancer cells: Fhit-tyrosine 114 (Y114) is essential." Semba S., Trapasso F., Fabbri M., McCorkell K.A., Volinia S., Druck T., Iliopoulos D., Pekarsky Y., Ishii H., Garrison P.N., Barnes L.D., Croce C.M., Huebner K. Oncogene 25:2860-2872(2006) [PubMed] [Europe PMC] [Abstract] Cited for: MUTAGENESIS OF TYR-114, FUNCTION.
[13]	"The tumor suppressor Fhit acts as a repressor of beta-catenin transcriptional activity." Weiske J., Albring K.F., Huber O. Proc. Natl. Acad. Sci. U.S.A. 104:20344-20349(2007) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH CTNNB1, IDENTIFICATION IN A COMPLEX WITH CTNNB1 AND LEF1, FUNCTION.
[14]	"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] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[15]	"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] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS).
[16]	"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] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) IN COMPLEXES WITH SUBSTRATES, CATALYTIC ACTIVITY, FUNCTION, SUBUNIT, ACTIVE SITE.
[17]	"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] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) IN COMPLEXES WITH SUBSTRATE ANALOGS, SUBUNIT, CATALYTIC ACTIVITY, COFACTOR, MUTAGENESIS OF HIS-96.
+	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.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-29947N.

IntAct

P49789. 8 interactions.

MINT

MINT-150697.

STRING

9606.ENSP00000342087.

PTM databases

PhosphoSite

P49789.

Polymorphism databases

DMDM

1706794.

Proteomic databases

PaxDb

P49789.

PeptideAtlas

P49789.

PRIDE

P49789.

Protocols and materials databases

DNASU

2272.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000341848; ENSP00000342087; ENSG00000189283.
ENST00000468189; ENSP00000417480; ENSG00000189283.
ENST00000476844; ENSP00000417557; ENSG00000189283.
ENST00000492590; ENSP00000418582; ENSG00000189283.
ENST00000571334; ENSP00000458888; ENSG00000262683.
ENST00000571653; ENSP00000460853; ENSG00000262683.
ENST00000573237; ENSP00000461165; ENSG00000262683.

GeneID

2272.

KEGG

hsa:2272.

UCSC

uc003dkx.4. human.

Organism-specific databases

CTD

2272.

GeneCards

GC03M059712.

HGNC

HGNC:3701. FHIT.

HPA

CAB002684.
HPA018840.
HPA018909.

MIM

601153. gene.

neXtProt

NX_P49789.

Orphanet

151. Familial renal cell carcinoma.

PharmGKB

PA28140.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0537.

HOGENOM

HOG000164170.

HOVERGEN

HBG051614.

InParanoid

P49789.

KO

K01522.

OMA

TLWRSEE.

OrthoDB

EOG4GQQ68.

PhylomeDB

P49789.

Enzyme and pathway databases

SABIO-RK

P49789.

Gene expression databases

ArrayExpress

P49789.

Bgee

P49789.

CleanEx

HS_FHIT.

Genevestigator

P49789.

Family and domain databases

Gene3D

3.30.428.10. 1 hit.

InterPro

IPR019808. Histidine_triad_CS.
IPR001310. Histidine_triad_HIT.
IPR011146. HIT-like.
[Graphical view]

PANTHER

PTHR23089. PTHR23089. 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

BindingDB

P49789.

ChEMBL

CHEMBL1795151.

ChiTaRS

FHIT. human.

EvolutionaryTrace

P49789.

GenomeRNAi

2272.

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:	May 1, 2013
This is version 128 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.