Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.
Protein

Bis(5'-adenosyl)-triphosphatase

Gene

FHIT

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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, it may in part come from the mitochondrial form, which sensitizes the low-affinity Ca2+ transporters, enhancing mitochondrial calcium uptake. Functions as tumor suppressor.7 Publications

Catalytic activityi

P(1)-P(3)-bis(5'-adenosyl) triphosphate + H2O = ADP + AMP.5 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei8SubstrateCombined sources1 Publication1
Binding sitei27SubstrateCombined sources1 Publication1
Binding sitei83SubstrateCombined sources1 Publication1
Active sitei96Tele-AMP-histidine intermediate2 Publications1
Binding sitei98SubstrateCombined sources1 Publication1
Sitei114Important for induction of apoptosis1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi89 – 92SubstrateCombined sources1 Publication4

GO - Molecular functioni

  • bis(5'-adenosyl)-triphosphatase activity Source: UniProtKB
  • catalytic activity Source: ProtInc
  • hydrolase activity Source: UniProtKB
  • identical protein binding Source: IntAct
  • nucleotide binding Source: UniProtKB-KW
  • ubiquitin protein ligase binding Source: UniProtKB

GO - Biological processi

  • intrinsic apoptotic signaling pathway by p53 class mediator Source: UniProtKB
  • negative regulation of proteasomal ubiquitin-dependent protein catabolic process Source: UniProtKB
  • nucleotide metabolic process Source: ProtInc
  • purine nucleotide metabolic process Source: UniProtKB
  • regulation of transcription, DNA-templated Source: UniProtKB-KW
  • transcription, DNA-templated Source: UniProtKB-KW
Complete GO annotation...

Keywords - Molecular functioni

Hydrolase

Keywords - Biological processi

Apoptosis, Transcription, Transcription regulation

Keywords - Ligandi

Manganese, Nucleotide-binding

Enzyme and pathway databases

BioCyciZFISH:HS00015-MONOMER.
BRENDAi3.6.1.29. 2681.
SABIO-RKP49789.
SIGNORiP49789.

Names & Taxonomyi

Protein namesi
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 namesi
Name:FHIT
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 3

Organism-specific databases

HGNCiHGNC:3701. FHIT.

Subcellular locationi

GO - Cellular componenti

  • cytoplasm Source: UniProtKB
  • cytosol Source: UniProtKB
  • extracellular exosome Source: UniProtKB
  • mitochondrion Source: UniProtKB-SubCell
  • nucleus Source: UniProtKB-SubCell
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Mitochondrion, Nucleus

Pathology & Biotechi

Involvement in diseasei

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.

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.

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi10I → W: Strongly reduces affinity for substrates and impairs apoptosis; when associated with W-25. 1 Publication1
Mutagenesisi25L → W: Reduces affinity for substrates and impairs apoptosis. Strongly reduces affinity for substrates and impairs apoptosis; when associated with W-10. 1 Publication1
Mutagenesisi35H → N: 50% decrease in catalytic activity. No loss in substrate binding. 1 Publication1
Mutagenesisi94H → N: 75% decrease in catalytic activity. No loss in substrate binding. 1 Publication1
Mutagenesisi96H → D: Loss of catalytic activity. 4 Publications1
Mutagenesisi96H → G: Total loss of catalytic activity. Rescuable with free imidazole. 4 Publications1
Mutagenesisi96H → N: Total loss of catalytic activity. No loss in substrate binding. 4 Publications1
Mutagenesisi98H → N: 98% decrease in catalytic activity. 1 Publication1
Mutagenesisi114Y → A: Impairs induction of apoptosis. Strongly reduced affinity for substrates. 2 Publications1
Mutagenesisi114Y → D: Impairs induction of apoptosis. Reduces affinity for substrates. 2 Publications1
Mutagenesisi114Y → F: Loss of phosphorylation by SRC. Impairs induction of apoptosis. 2 Publications1
Mutagenesisi145Y → F: No effect on phosphorylation by SRC. 1 Publication1

Keywords - Diseasei

Tumor suppressor

Organism-specific databases

DisGeNETi2272.
OpenTargetsiENSG00000189283.
Orphaneti151. Familial renal cell carcinoma.
PharmGKBiPA28140.

Chemistry databases

ChEMBLiCHEMBL1795151.

Polymorphism and mutation databases

BioMutaiFHIT.
DMDMi1706794.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001097891 – 147Bis(5'-adenosyl)-triphosphataseAdd BLAST147

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei114Phosphotyrosine; by SRC1 Publication1
Modified residuei145Phosphotyrosine1 Publication1

Post-translational modificationi

Phosphorylation at Tyr-114 by SRC is required for induction of apoptosis.1 Publication

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiP49789.
PaxDbiP49789.
PeptideAtlasiP49789.
PRIDEiP49789.

PTM databases

iPTMnetiP49789.
PhosphoSitePlusiP49789.

Expressioni

Tissue specificityi

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.

Gene expression databases

BgeeiENSG00000189283.
CleanExiHS_FHIT.
ExpressionAtlasiP49789. baseline and differential.
GenevisibleiP49789. HS.

Organism-specific databases

HPAiCAB002684.
HPA018840.
HPA018909.

Interactioni

Subunit structurei

Homodimer. Interacts with UBE2I. Interacts with MDM2. Interacts with CTNNB1. Identified in a complex with CTNNB1 and LEF1.6 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
itself8EBI-741760,EBI-741760
FDXRP225704EBI-741760,EBI-1751533
HSPD1P108095EBI-741760,EBI-352528
HSPE1P616044EBI-741760,EBI-711483

GO - Molecular functioni

  • identical protein binding Source: IntAct
  • ubiquitin protein ligase binding Source: UniProtKB

Protein-protein interaction databases

BioGridi108563. 12 interactors.
DIPiDIP-29947N.
IntActiP49789. 8 interactors.
MINTiMINT-150697.
STRINGi9606.ENSP00000342087.

Chemistry databases

BindingDBiP49789.

Structurei

Secondary structure

1147
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi3 – 5Combined sources3
Beta strandi8 – 10Combined sources3
Helixi12 – 14Combined sources3
Beta strandi15 – 18Combined sources4
Beta strandi20 – 26Combined sources7
Beta strandi36 – 42Combined sources7
Helixi47 – 49Combined sources3
Helixi52 – 72Combined sources21
Beta strandi76 – 82Combined sources7
Helixi86 – 88Combined sources3
Beta strandi92 – 94Combined sources3
Beta strandi97 – 102Combined sources6
Helixi132 – 144Combined sources13

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1FHIX-ray3.10A1-147[»]
1FITX-ray1.85A1-147[»]
2FHIX-ray2.60A1-147[»]
2FITX-ray1.90A1-147[»]
3FITX-ray2.40A1-147[»]
4FITX-ray2.50A1-147[»]
5FITX-ray2.30A1-147[»]
6FITX-ray2.60A1-147[»]
ProteinModelPortaliP49789.
SMRiP49789.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP49789.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini2 – 109HITPROSITE-ProRule annotationAdd BLAST108

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi94 – 98Histidine triad motifPROSITE-ProRule annotation5

Sequence similaritiesi

Contains 1 HIT domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG3379. Eukaryota.
COG0537. LUCA.
GeneTreeiENSGT00510000047967.
HOGENOMiHOG000164170.
HOVERGENiHBG051614.
KOiK01522.
OMAiWANNDDI.
OrthoDBiEOG091G0RR0.
PhylomeDBiP49789.
TreeFamiTF105432.

Family and domain databases

Gene3Di3.30.428.10. 1 hit.
InterProiIPR019808. Histidine_triad_CS.
IPR001310. Histidine_triad_HIT.
IPR011146. HIT-like.
[Graphical view]
PANTHERiPTHR23089. PTHR23089. 1 hit.
PfamiPF01230. HIT. 1 hit.
[Graphical view]
SUPFAMiSSF54197. SSF54197. 1 hit.
PROSITEiPS00892. HIT_1. 1 hit.
PS51084. HIT_2. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

P49789-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSFRFGQHLI KPSVVFLKTE LSFALVNRKP VVPGHVLVCP LRPVERFHDL
60 70 80 90 100
RPDEVADLFQ TTQRVGTVVE KHFHGTSLTF SMQDGPEAGQ TVKHVHVHVL
110 120 130 140
PRKAGDFHRN DSIYEELQKH DKEDFPASWR SEEEMAAEAA ALRVYFQ
Length:147
Mass (Da):16,858
Last modified:January 23, 2007 - v3
Checksum:i14D85961A19ECF3E
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti146F → S in BAF82513 (PubMed:14702039).Curated1

Mass spectrometryi

Molecular mass is 16733 Da from positions 2 - 147. Determined by MALDI. 1 Publication

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U46922 mRNA. Translation: AAA99013.1.
U76271
, U76267, U76268, U76269, U76270 Genomic DNA. Translation: AAB52539.1.
KJ534835 mRNA. Translation: AHW56475.1.
AY625256 Genomic DNA. Translation: AAT37530.1.
DQ120721 mRNA. Translation: AAZ23623.1.
EF186677 Genomic DNA. Translation: ABM65879.1.
EF183457 Genomic DNA. Translation: ABM66086.1.
EF183458 Genomic DNA. Translation: ABM66087.1.
EF183459 Genomic DNA. Translation: ABM66088.1.
EF183461 Genomic DNA. Translation: ABM66090.1.
EF183464 Genomic DNA. Translation: ABM66093.1.
AK289824 mRNA. Translation: BAF82513.1.
CH471055 Genomic DNA. Translation: EAW65393.1.
BC032336 mRNA. Translation: AAH32336.1.
CCDSiCCDS2894.1.
PIRiA58802.
RefSeqiNP_001159715.1. NM_001166243.2.
NP_001307828.1. NM_001320899.1.
NP_001307829.1. NM_001320900.1.
NP_002003.1. NM_002012.3.
UniGeneiHs.655995.

Genome annotation databases

EnsembliENST00000468189; ENSP00000417480; ENSG00000189283.
ENST00000476844; ENSP00000417557; ENSG00000189283.
ENST00000492590; ENSP00000418582; ENSG00000189283.
GeneIDi2272.
KEGGihsa:2272.
UCSCiuc003dkx.5. human.

Keywords - Coding sequence diversityi

Chromosomal rearrangement

Cross-referencesi

Web resourcesi

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U46922 mRNA. Translation: AAA99013.1.
U76271
, U76267, U76268, U76269, U76270 Genomic DNA. Translation: AAB52539.1.
KJ534835 mRNA. Translation: AHW56475.1.
AY625256 Genomic DNA. Translation: AAT37530.1.
DQ120721 mRNA. Translation: AAZ23623.1.
EF186677 Genomic DNA. Translation: ABM65879.1.
EF183457 Genomic DNA. Translation: ABM66086.1.
EF183458 Genomic DNA. Translation: ABM66087.1.
EF183459 Genomic DNA. Translation: ABM66088.1.
EF183461 Genomic DNA. Translation: ABM66090.1.
EF183464 Genomic DNA. Translation: ABM66093.1.
AK289824 mRNA. Translation: BAF82513.1.
CH471055 Genomic DNA. Translation: EAW65393.1.
BC032336 mRNA. Translation: AAH32336.1.
CCDSiCCDS2894.1.
PIRiA58802.
RefSeqiNP_001159715.1. NM_001166243.2.
NP_001307828.1. NM_001320899.1.
NP_001307829.1. NM_001320900.1.
NP_002003.1. NM_002012.3.
UniGeneiHs.655995.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1FHIX-ray3.10A1-147[»]
1FITX-ray1.85A1-147[»]
2FHIX-ray2.60A1-147[»]
2FITX-ray1.90A1-147[»]
3FITX-ray2.40A1-147[»]
4FITX-ray2.50A1-147[»]
5FITX-ray2.30A1-147[»]
6FITX-ray2.60A1-147[»]
ProteinModelPortaliP49789.
SMRiP49789.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi108563. 12 interactors.
DIPiDIP-29947N.
IntActiP49789. 8 interactors.
MINTiMINT-150697.
STRINGi9606.ENSP00000342087.

Chemistry databases

BindingDBiP49789.
ChEMBLiCHEMBL1795151.

PTM databases

iPTMnetiP49789.
PhosphoSitePlusiP49789.

Polymorphism and mutation databases

BioMutaiFHIT.
DMDMi1706794.

Proteomic databases

EPDiP49789.
PaxDbiP49789.
PeptideAtlasiP49789.
PRIDEiP49789.

Protocols and materials databases

DNASUi2272.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000468189; ENSP00000417480; ENSG00000189283.
ENST00000476844; ENSP00000417557; ENSG00000189283.
ENST00000492590; ENSP00000418582; ENSG00000189283.
GeneIDi2272.
KEGGihsa:2272.
UCSCiuc003dkx.5. human.

Organism-specific databases

CTDi2272.
DisGeNETi2272.
GeneCardsiFHIT.
HGNCiHGNC:3701. FHIT.
HPAiCAB002684.
HPA018840.
HPA018909.
MIMi601153. gene.
neXtProtiNX_P49789.
OpenTargetsiENSG00000189283.
Orphaneti151. Familial renal cell carcinoma.
PharmGKBiPA28140.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG3379. Eukaryota.
COG0537. LUCA.
GeneTreeiENSGT00510000047967.
HOGENOMiHOG000164170.
HOVERGENiHBG051614.
KOiK01522.
OMAiWANNDDI.
OrthoDBiEOG091G0RR0.
PhylomeDBiP49789.
TreeFamiTF105432.

Enzyme and pathway databases

BioCyciZFISH:HS00015-MONOMER.
BRENDAi3.6.1.29. 2681.
SABIO-RKP49789.
SIGNORiP49789.

Miscellaneous databases

ChiTaRSiFHIT. human.
EvolutionaryTraceiP49789.
GeneWikiiFHIT.
GenomeRNAii2272.
PROiP49789.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000189283.
CleanExiHS_FHIT.
ExpressionAtlasiP49789. baseline and differential.
GenevisibleiP49789. HS.

Family and domain databases

Gene3Di3.30.428.10. 1 hit.
InterProiIPR019808. Histidine_triad_CS.
IPR001310. Histidine_triad_HIT.
IPR011146. HIT-like.
[Graphical view]
PANTHERiPTHR23089. PTHR23089. 1 hit.
PfamiPF01230. HIT. 1 hit.
[Graphical view]
SUPFAMiSSF54197. SSF54197. 1 hit.
PROSITEiPS00892. HIT_1. 1 hit.
PS51084. HIT_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiFHIT_HUMAN
AccessioniPrimary (citable) accession number: P49789
Secondary accession number(s): A2IAS9
, A2IAT0, A2IAT6, A8K1A9, Q45QG9, Q6IU12
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: January 23, 2007
Last modified: November 30, 2016
This is version 160 of the entry and version 3 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 3
    Human chromosome 3: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  4. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.