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Protein

Bis(5'-adenosyl)-triphosphatase

Gene

FHIT

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

Functioni

Cleaves P1-P3-bis(5'-adenosyl) triphosphate (Ap3A) to yield AMP and ADP. Can also hydrolyze P1-P4-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 P1-P3-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

P1-P3-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

Keywordsi

Molecular functionHydrolase
Biological processApoptosis, Transcription, Transcription regulation
LigandManganese, Nucleotide-binding

Enzyme and pathway databases

BRENDAi3.6.1.29 2681
SABIO-RKiP49789
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

EuPathDBiHostDB:ENSG00000189283.9
HGNCiHGNC:3701 FHIT
MIMi601153 gene
neXtProtiNX_P49789

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

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.1 Publication
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.1 Publication

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
MalaCardsiFHIT
OpenTargetsiENSG00000189283
Orphaneti151 Familial renal cell carcinoma
PharmGKBiPA28140

Chemistry databases

ChEMBLiCHEMBL1795151
DrugBankiDB02373 Adenosine Monotungstate
DB04389 Ado-P-Ch2-P-Ps-Ado
DB04173 Fructose

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
ProteomicsDBi56119

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

Show more details

GO - Molecular functioni

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

Protein-protein interaction databases

BioGridi108563, 14 interactors
DIPiDIP-29947N
IntActiP49789, 5 interactors
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

Phylogenomic databases

eggNOGiKOG3379 Eukaryota
COG0537 LUCA
GeneTreeiENSGT00510000047967
HOGENOMiHOG000164170
HOVERGENiHBG051614
KOiK01522
OMAiKFGPFEV
OrthoDBiEOG091G0RR0
PhylomeDBiP49789
TreeFamiTF105432

Family and domain databases

Gene3Di3.30.428.10, 1 hit
InterProiView protein in InterPro
IPR019808 Histidine_triad_CS
IPR001310 Histidine_triad_HIT
IPR011146 HIT-like
IPR036265 HIT-like_sf
PANTHERiPTHR23089 PTHR23089, 1 hit
PfamiView protein in Pfam
PF01230 HIT, 1 hit
SUPFAMiSSF54197 SSF54197, 1 hit
PROSITEiView protein in PROSITE
PS00892 HIT_1, 1 hit
PS51084 HIT_2, 1 hit

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

Similar proteinsi

Entry informationi

Entry nameiFHIT_HUMAN
AccessioniPrimary (citable) accession number: P49789
Secondary accession number(s): A2IAS9
, A2IAT0, A2IAT6, A8K1A9, Q45QG9, Q6IU12
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: January 23, 2007
Last modified: June 20, 2018
This is version 169 of the entry and version 3 of the sequence. See 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

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