UniProtKB - P49789 (FHIT_HUMAN)
Protein
Bis(5'-adenosyl)-triphosphatase
Gene
FHIT
Organism
Homo sapiens (Human)
Status
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
- EC:3.6.1.295 Publications
Sites
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Binding sitei | 8 | SubstrateCombined sources1 Publication | 1 | |
Binding sitei | 27 | SubstrateCombined sources1 Publication | 1 | |
Binding sitei | 83 | SubstrateCombined sources1 Publication | 1 | |
Active sitei | 96 | Tele-AMP-histidine intermediate2 Publications | 1 | |
Binding sitei | 98 | SubstrateCombined sources1 Publication | 1 | |
Sitei | 114 | Important for induction of apoptosis | 1 |
Regions
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Nucleotide bindingi | 89 – 92 | SubstrateCombined sources1 Publication | 4 |
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
- diadenosine triphosphate catabolic process Source: GO_Central
- 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
Keywordsi
Molecular function | Hydrolase |
Biological process | Apoptosis, Transcription, Transcription regulation |
Ligand | Manganese, Nucleotide-binding |
Enzyme and pathway databases
BRENDAi | 3.6.1.29, 2681 |
PathwayCommonsi | P49789 |
SABIO-RKi | P49789 |
SIGNORi | P49789 |
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 |
Organismi | Homo sapiens (Human) |
Taxonomic identifieri | 9606 [NCBI] |
Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Proteomesi |
|
Organism-specific databases
EuPathDBi | HostDB:ENSG00000189283.9 |
HGNCi | HGNC:3701, FHIT |
MIMi | 601153, gene |
neXtProti | NX_P49789 |
Subcellular locationi
Nucleus
Mitochondrion
Other locations
Cytosol
- cytosol Source: UniProtKB
Mitochondrion
- mitochondrion Source: UniProtKB-SubCell
Nucleus
- fibrillar center Source: HPA
- nucleus Source: GO_Central
Plasma Membrane
- plasma membrane Source: HPA
Other locations
- cytoplasm Source: UniProtKB
Keywords - Cellular componenti
Cytoplasm, Mitochondrion, NucleusPathology & 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 key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Mutagenesisi | 10 | I → W: Strongly reduces affinity for substrates and impairs apoptosis; when associated with W-25. 1 Publication | 1 | |
Mutagenesisi | 25 | L → W: Reduces affinity for substrates and impairs apoptosis. Strongly reduces affinity for substrates and impairs apoptosis; when associated with W-10. 1 Publication | 1 | |
Mutagenesisi | 35 | H → N: 50% decrease in catalytic activity. No loss in substrate binding. 1 Publication | 1 | |
Mutagenesisi | 94 | H → N: 75% decrease in catalytic activity. No loss in substrate binding. 1 Publication | 1 | |
Mutagenesisi | 96 | H → D: Loss of catalytic activity. 4 Publications | 1 | |
Mutagenesisi | 96 | H → G: Total loss of catalytic activity. Rescuable with free imidazole. 4 Publications | 1 | |
Mutagenesisi | 96 | H → N: Total loss of catalytic activity. No loss in substrate binding. 4 Publications | 1 | |
Mutagenesisi | 98 | H → N: 98% decrease in catalytic activity. 1 Publication | 1 | |
Mutagenesisi | 114 | Y → A: Impairs induction of apoptosis. Strongly reduced affinity for substrates. 2 Publications | 1 | |
Mutagenesisi | 114 | Y → D: Impairs induction of apoptosis. Reduces affinity for substrates. 2 Publications | 1 | |
Mutagenesisi | 114 | Y → F: Loss of phosphorylation by SRC. Impairs induction of apoptosis. 2 Publications | 1 | |
Mutagenesisi | 145 | Y → F: No effect on phosphorylation by SRC. 1 Publication | 1 |
Keywords - Diseasei
Tumor suppressorOrganism-specific databases
DisGeNETi | 2272 |
MalaCardsi | FHIT |
OpenTargetsi | ENSG00000189283 |
Orphaneti | 422526, Hereditary clear cell renal cell carcinoma |
PharmGKBi | PA28140 |
Miscellaneous databases
Pharosi | P49789, Tchem |
Chemistry databases
ChEMBLi | CHEMBL1795151 |
DrugBanki | DB02373, Adenosine monotungstate DB04389, Ado-P-Ch2-P-Ps-Ado |
Polymorphism and mutation databases
BioMutai | FHIT |
DMDMi | 1706794 |
PTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
ChainiPRO_0000109789 | 1 – 147 | Bis(5'-adenosyl)-triphosphataseAdd BLAST | 147 |
Amino acid modifications
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Modified residuei | 114 | Phosphotyrosine; by SRC1 Publication | 1 | |
Modified residuei | 145 | Phosphotyrosine1 Publication | 1 |
Post-translational modificationi
Phosphorylation at Tyr-114 by SRC is required for induction of apoptosis.1 Publication
Keywords - PTMi
PhosphoproteinProteomic databases
EPDi | P49789 |
jPOSTi | P49789 |
MassIVEi | P49789 |
PaxDbi | P49789 |
PeptideAtlasi | P49789 |
PRIDEi | P49789 |
ProteomicsDBi | 56119 |
PTM databases
iPTMneti | P49789 |
PhosphoSitePlusi | P49789 |
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
Bgeei | ENSG00000189283, Expressed in pigmented layer of retina and 149 other tissues |
ExpressionAtlasi | P49789, baseline and differential |
Genevisiblei | P49789, HS |
Organism-specific databases
HPAi | ENSG00000189283, Low tissue specificity |
Interactioni
Subunit structurei
Homodimer.
Interacts with UBE2I.
Interacts with MDM2.
Interacts with CTNNB1.
Identified in a complex with CTNNB1 and LEF1.
6 PublicationsBinary interactionsi
Hide detailsP49789
With | #Exp. | IntAct |
---|---|---|
CTNNB1 [P35222] | 4 | EBI-741760,EBI-491549 |
DDIT4L [Q96D03] | 3 | EBI-741760,EBI-742054 |
itself | 13 | EBI-741760,EBI-741760 |
LEF1 [Q9UJU2] | 2 | EBI-741760,EBI-926131 |
GO - Molecular functioni
- identical protein binding Source: IntAct
- ubiquitin protein ligase binding Source: UniProtKB
Protein-protein interaction databases
BioGRIDi | 108563, 15 interactors |
DIPi | DIP-29947N |
IntActi | P49789, 9 interactors |
STRINGi | 9606.ENSP00000417480 |
Chemistry databases
BindingDBi | P49789 |
Miscellaneous databases
RNActi | P49789, protein |
Structurei
Secondary structure
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details3D structure databases
SMRi | P49789 |
ModBasei | Search... |
PDBe-KBi | Search... |
Miscellaneous databases
EvolutionaryTracei | P49789 |
Family & Domainsi
Domains and Repeats
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Domaini | 2 – 109 | HITPROSITE-ProRule annotationAdd BLAST | 108 |
Motif
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Motifi | 94 – 98 | Histidine triad motifPROSITE-ProRule annotation | 5 |
Phylogenomic databases
eggNOGi | KOG3379, Eukaryota |
GeneTreei | ENSGT00510000047967 |
HOGENOMi | CLU_056776_7_1_1 |
OMAi | VHTHIIP |
OrthoDBi | 1198291at2759 |
PhylomeDBi | P49789 |
TreeFami | TF105432 |
Family and domain databases
CDDi | cd01275, FHIT, 1 hit |
Gene3Di | 3.30.428.10, 1 hit |
InterProi | View protein in InterPro IPR039383, FHIT IPR019808, Histidine_triad_CS IPR001310, Histidine_triad_HIT IPR011146, HIT-like IPR036265, HIT-like_sf |
Pfami | View protein in Pfam PF01230, HIT, 1 hit |
SUPFAMi | SSF54197, SSF54197, 1 hit |
PROSITEi | View protein in PROSITE PS00892, HIT_1, 1 hit PS51084, HIT_2, 1 hit |
(1+)i Sequence
Sequence statusi: Complete.
This entry has 1 described isoform and 2 potential isoforms that are computationally mapped.Show allAlign All
P49789-1 [UniParc]FASTAAdd to basket
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
Computationally mapped potential isoform sequencesi
There are 2 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basketE9PBZ0 | E9PBZ0_HUMAN | Bis(5'-adenosyl)-triphosphatase | FHIT | 78 | Annotation score: | ||
A0A0A0MRB0 | A0A0A0MRB0_HUMAN | Bis(5'-adenosyl)-triphosphatase | FHIT | 58 | Annotation score: |
Experimental Info
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Sequence conflicti | 146 | F → S in BAF82513 (PubMed:14702039).Curated | 1 |
Mass spectrometryi
Molecular mass is 16733 Da. 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 |
CCDSi | CCDS2894.1 |
PIRi | A58802 |
RefSeqi | NP_001159715.1, NM_001166243.2 NP_001307828.1, NM_001320899.1 NP_001307829.1, NM_001320900.1 NP_002003.1, NM_002012.3 |
Genome annotation databases
Ensembli | ENST00000468189; ENSP00000417480; ENSG00000189283 ENST00000476844; ENSP00000417557; ENSG00000189283 ENST00000492590; ENSP00000418582; ENSG00000189283 |
GeneIDi | 2272 |
KEGGi | hsa:2272 |
UCSCi | uc003dkx.5, human |
Keywords - Coding sequence diversityi
Chromosomal rearrangementSimilar proteinsi
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 |
CCDSi | CCDS2894.1 |
PIRi | A58802 |
RefSeqi | NP_001159715.1, NM_001166243.2 NP_001307828.1, NM_001320899.1 NP_001307829.1, NM_001320900.1 NP_002003.1, NM_002012.3 |
3D structure databases
Select the link destinations: PDBei RCSB PDBi PDBji Links Updated | PDB 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 | [»] | |
SMRi | P49789 | |||||
ModBasei | Search... | |||||
PDBe-KBi | Search... |
Protein-protein interaction databases
BioGRIDi | 108563, 15 interactors |
DIPi | DIP-29947N |
IntActi | P49789, 9 interactors |
STRINGi | 9606.ENSP00000417480 |
Chemistry databases
BindingDBi | P49789 |
ChEMBLi | CHEMBL1795151 |
DrugBanki | DB02373, Adenosine monotungstate DB04389, Ado-P-Ch2-P-Ps-Ado |
PTM databases
iPTMneti | P49789 |
PhosphoSitePlusi | P49789 |
Polymorphism and mutation databases
BioMutai | FHIT |
DMDMi | 1706794 |
Proteomic databases
EPDi | P49789 |
jPOSTi | P49789 |
MassIVEi | P49789 |
PaxDbi | P49789 |
PeptideAtlasi | P49789 |
PRIDEi | P49789 |
ProteomicsDBi | 56119 |
Protocols and materials databases
Antibodypediai | 3636, 591 antibodies |
DNASUi | 2272 |
Genome annotation databases
Ensembli | ENST00000468189; ENSP00000417480; ENSG00000189283 ENST00000476844; ENSP00000417557; ENSG00000189283 ENST00000492590; ENSP00000418582; ENSG00000189283 |
GeneIDi | 2272 |
KEGGi | hsa:2272 |
UCSCi | uc003dkx.5, human |
Organism-specific databases
CTDi | 2272 |
DisGeNETi | 2272 |
EuPathDBi | HostDB:ENSG00000189283.9 |
GeneCardsi | FHIT |
HGNCi | HGNC:3701, FHIT |
HPAi | ENSG00000189283, Low tissue specificity |
MalaCardsi | FHIT |
MIMi | 601153, gene |
neXtProti | NX_P49789 |
OpenTargetsi | ENSG00000189283 |
Orphaneti | 422526, Hereditary clear cell renal cell carcinoma |
PharmGKBi | PA28140 |
GenAtlasi | Search... |
Phylogenomic databases
eggNOGi | KOG3379, Eukaryota |
GeneTreei | ENSGT00510000047967 |
HOGENOMi | CLU_056776_7_1_1 |
OMAi | VHTHIIP |
OrthoDBi | 1198291at2759 |
PhylomeDBi | P49789 |
TreeFami | TF105432 |
Enzyme and pathway databases
BRENDAi | 3.6.1.29, 2681 |
PathwayCommonsi | P49789 |
SABIO-RKi | P49789 |
SIGNORi | P49789 |
Miscellaneous databases
BioGRID-ORCSi | 2272, 7 hits in 849 CRISPR screens |
ChiTaRSi | FHIT, human |
EvolutionaryTracei | P49789 |
GeneWikii | FHIT |
GenomeRNAii | 2272 |
Pharosi | P49789, Tchem |
PROi | PR:P49789 |
RNActi | P49789, protein |
SOURCEi | Search... |
Gene expression databases
Bgeei | ENSG00000189283, Expressed in pigmented layer of retina and 149 other tissues |
ExpressionAtlasi | P49789, baseline and differential |
Genevisiblei | P49789, HS |
Family and domain databases
CDDi | cd01275, FHIT, 1 hit |
Gene3Di | 3.30.428.10, 1 hit |
InterProi | View protein in InterPro IPR039383, FHIT IPR019808, Histidine_triad_CS IPR001310, Histidine_triad_HIT IPR011146, HIT-like IPR036265, HIT-like_sf |
Pfami | View protein in Pfam PF01230, HIT, 1 hit |
SUPFAMi | SSF54197, SSF54197, 1 hit |
PROSITEi | View protein in PROSITE PS00892, HIT_1, 1 hit PS51084, HIT_2, 1 hit |
ProtoNeti | Search... |
MobiDBi | Search... |
Entry informationi
Entry namei | FHIT_HUMAN | |
Accessioni | P49789Primary (citable) accession number: P49789 Secondary accession number(s): A2IAS9 Q6IU12 | |
Entry historyi | Integrated into UniProtKB/Swiss-Prot: | October 1, 1996 |
Last sequence update: | January 23, 2007 | |
Last modified: | December 2, 2020 | |
This is version 186 of the entry and version 3 of the sequence. See complete history. | ||
Entry statusi | 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. |
Miscellaneousi
Keywords - Technical termi
3D-structure, Reference proteomeDocuments
- Human chromosome 3
Human chromosome 3: entries, gene names and cross-references to MIM - MIM cross-references
Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot - PDB cross-references
Index of Protein Data Bank (PDB) cross-references