HINT1_MOUSE
ID HINT1_MOUSE Reviewed; 126 AA.
AC P70349;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 3.
DT 03-AUG-2022, entry version 167.
DE RecName: Full=Adenosine 5'-monophosphoramidase HINT1 {ECO:0000250|UniProtKB:P49773};
DE EC=3.9.1.- {ECO:0000250|UniProtKB:P49773};
DE AltName: Full=Desumoylating isopeptidase HINT1 {ECO:0000305|PubMed:31088288};
DE EC=3.4.22.- {ECO:0000250|UniProtKB:P49773};
DE AltName: Full=Histidine triad nucleotide-binding protein 1;
DE AltName: Full=Protein kinase C inhibitor 1;
DE AltName: Full=Protein kinase C-interacting protein 1;
DE Short=PKCI-1;
GN Name=Hint1; Synonyms=Hint, Pkci, Pkci1, Prkcnh1;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=NIH Swiss;
RX PubMed=9770345; DOI=10.1006/excr.1998.4153;
RA Klein M.G., Yao Y., Slosberg E.D., Lima C.D., Doki Y., Weinstein I.B.;
RT "Characterization of PKCI and comparative studies with FHIT, related
RT members of the HIT protein family.";
RL Exp. Cell Res. 244:26-32(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Brain;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP PROTEIN SEQUENCE OF 8-21; 38-57 AND 96-119, AND IDENTIFICATION BY MASS
RP SPECTROMETRY.
RC TISSUE=Hippocampus;
RA Lubec G., Klug S.;
RL Submitted (MAR-2007) to UniProtKB.
RN [5]
RP DISRUPTION PHENOTYPE.
RX PubMed=12810953; DOI=10.1073/pnas.1332160100;
RA Su T., Suzui M., Wang L., Lin C.S., Xing W.Q., Weinstein I.B.;
RT "Deletion of histidine triad nucleotide-binding protein 1/PKC-interacting
RT protein in mice enhances cell growth and carcinogenesis.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:7824-7829(2003).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-45 AND SER-72, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Liver, Lung, Pancreas,
RC Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [7]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-21, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic fibroblast;
RX PubMed=23806337; DOI=10.1016/j.molcel.2013.06.001;
RA Park J., Chen Y., Tishkoff D.X., Peng C., Tan M., Dai L., Xie Z., Zhang Y.,
RA Zwaans B.M., Skinner M.E., Lombard D.B., Zhao Y.;
RT "SIRT5-mediated lysine desuccinylation impacts diverse metabolic
RT pathways.";
RL Mol. Cell 50:919-930(2013).
RN [8]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, INTERACTION WITH SUMO1;
RP SUMO2; CALM1; RGS17 AND TENM1, AND MUTAGENESIS OF THR-17; CYS-38; CYS-84;
RP ASP-87; HIS-112; HIS-114; VAL-115 AND LEU-116.
RX PubMed=31088288; DOI=10.1089/ars.2019.7724;
RA Cortes-Montero E., Rodriguez-Munoz M., Sanchez-Blazquez P., Garzon J.;
RT "The Axonal Motor Neuropathy-Related HINT1 Protein Is a Zinc- and
RT Calmodulin-Regulated Cysteine SUMO Protease.";
RL Antioxid. Redox Signal. 31:503-520(2019).
CC -!- FUNCTION: Exhibits adenosine 5'-monophosphoramidase activity,
CC hydrolyzing purine nucleotide phosphoramidates with a single phosphate
CC group such as adenosine 5'monophosphoramidate (AMP-NH2) to yield AMP
CC and NH2 (By similarity). Hydrolyzes adenosine 5'monophosphomorpholidate
CC (AMP-morpholidate) and guanosine 5'monophosphomorpholidate (GMP-
CC morpholidate) (By similarity). Hydrolyzes lysyl-AMP (AMP-N-epsilon-(N-
CC alpha-acetyl lysine methyl ester)) generated by lysine tRNA ligase, as
CC well as Met-AMP, His-AMP and Asp-AMP, lysyl-GMP (GMP-N-epsilon-(N-
CC alpha-acetyl lysine methyl ester)) and AMP-N-alanine methyl ester (By
CC similarity). Can also convert adenosine 5'-O-phosphorothioate and
CC guanosine 5'-O-phosphorothioate to the corresponding nucleoside 5'-O-
CC phosphates with concomitant release of hydrogen sulfide (By
CC similarity). In addition, functions as scaffolding protein that
CC modulates transcriptional activation by the LEF1/TCF1-CTNNB1 complex
CC and by the complex formed with MITF and CTNNB1 (By similarity).
CC Modulates p53/TP53 levels and p53/TP53-mediated apoptosis. Modulates
CC proteasomal degradation of target proteins by the SCF (SKP2-CUL1-F-box
CC protein) E3 ubiquitin-protein ligase complex (By similarity). Also
CC exhibits SUMO-specific isopeptidase activity, deconjugating SUMO1 from
CC RANGAP1 and RGS17 (PubMed:31088288). {ECO:0000250|UniProtKB:P49773,
CC ECO:0000269|PubMed:31088288}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=adenosine 5'-phosphoramidate + H2O = AMP + NH4(+);
CC Xref=Rhea:RHEA:67916, ChEBI:CHEBI:15377, ChEBI:CHEBI:28938,
CC ChEBI:CHEBI:57890, ChEBI:CHEBI:456215;
CC Evidence={ECO:0000250|UniProtKB:P49773};
CC -!- ACTIVITY REGULATION: Desumoylase activity is inhibited by zinc ions,
CC and inhibition is released by nitric oxide or calcium-activated
CC calmodulin. {ECO:0000269|PubMed:31088288}.
CC -!- SUBUNIT: Homodimer (By similarity). Interacts with CDK7 (By
CC similarity). Interacts with RUVBL1 and RUVBL2 and is associated with
CC the LEF1/TCF1-CTNNB1 complex and with a KAT5 histone acetyltransferase
CC complex (By similarity). Identified in a complex with MITF and CTNNB1
CC (By similarity). Interacts with CDC34 and RBX1, and is part of a SCF
CC (SKP2-CUL1-F-box protein) E3 ubiquitin-protein ligase complex (By
CC similarity). Interacts with SUMO1, SUMO2 and RGS17 (PubMed:31088288).
CC Interacts with the Ten-1 ICD form of TENM1 (PubMed:31088288). Interacts
CC with CALM1; interaction increases in the presence of calcium ions
CC (PubMed:31088288). {ECO:0000250|UniProtKB:P49773,
CC ECO:0000269|PubMed:31088288}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P49773}. Nucleus
CC {ECO:0000250|UniProtKB:P49773}.
CC -!- DISRUPTION PHENOTYPE: No visible phenotype. Mice display increased
CC susceptibility to carcinogens. {ECO:0000269|PubMed:12810953}.
CC -!- SIMILARITY: Belongs to the HINT family. {ECO:0000305}.
CC -!- CAUTION: Was originally thought to be a protein kinase C inhibitor and
CC to bind zinc in solution. Both seem to be incorrect. {ECO:0000305}.
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DR EMBL; U60001; AAC71076.1; -; mRNA.
DR EMBL; AK002965; BAB22484.1; -; mRNA.
DR EMBL; AK012433; BAB28235.1; -; mRNA.
DR EMBL; BC070415; AAH70415.1; -; mRNA.
DR EMBL; BC080296; AAH80296.1; -; mRNA.
DR CCDS; CCDS24702.1; -.
DR PIR; PN0044; PN0044.
DR RefSeq; NP_032274.1; NM_008248.2.
DR AlphaFoldDB; P70349; -.
DR BMRB; P70349; -.
DR SMR; P70349; -.
DR BioGRID; 200305; 8.
DR IntAct; P70349; 1.
DR STRING; 10090.ENSMUSP00000020504; -.
DR ChEMBL; CHEMBL1250364; -.
DR iPTMnet; P70349; -.
DR PhosphoSitePlus; P70349; -.
DR SwissPalm; P70349; -.
DR REPRODUCTION-2DPAGE; P70349; -.
DR EPD; P70349; -.
DR jPOST; P70349; -.
DR MaxQB; P70349; -.
DR PaxDb; P70349; -.
DR PeptideAtlas; P70349; -.
DR PRIDE; P70349; -.
DR ProteomicsDB; 269568; -.
DR Antibodypedia; 25857; 299 antibodies from 37 providers.
DR DNASU; 15254; -.
DR Ensembl; ENSMUST00000020504; ENSMUSP00000020504; ENSMUSG00000020267.
DR GeneID; 15254; -.
DR KEGG; mmu:15254; -.
DR UCSC; uc007iyj.1; mouse.
DR CTD; 3094; -.
DR MGI; MGI:1321133; Hint1.
DR VEuPathDB; HostDB:ENSMUSG00000020267; -.
DR eggNOG; KOG3275; Eukaryota.
DR GeneTree; ENSGT00940000154451; -.
DR HOGENOM; CLU_056776_8_1_1; -.
DR InParanoid; P70349; -.
DR OMA; YHLHAHL; -.
DR OrthoDB; 1190598at2759; -.
DR PhylomeDB; P70349; -.
DR TreeFam; TF314862; -.
DR BioGRID-ORCS; 15254; 4 hits in 74 CRISPR screens.
DR ChiTaRS; Hint1; mouse.
DR PRO; PR:P70349; -.
DR Proteomes; UP000000589; Chromosome 11.
DR RNAct; P70349; protein.
DR Bgee; ENSMUSG00000020267; Expressed in indifferent gonad and 258 other tissues.
DR ExpressionAtlas; P70349; baseline and differential.
DR Genevisible; P70349; MM.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0000118; C:histone deacetylase complex; ISS:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; IDA:MGI.
DR GO; GO:0005886; C:plasma membrane; ISO:MGI.
DR GO; GO:0043530; F:adenosine 5'-monophosphoramidase activity; ISS:UniProtKB.
DR GO; GO:0016929; F:deSUMOylase activity; IDA:UniProtKB.
DR GO; GO:0016787; F:hydrolase activity; ISS:UniProtKB.
DR GO; GO:0000166; F:nucleotide binding; IEA:UniProtKB-KW.
DR GO; GO:0072332; P:intrinsic apoptotic signaling pathway by p53 class mediator; ISS:UniProtKB.
DR GO; GO:0050850; P:positive regulation of calcium-mediated signaling; IMP:CACAO.
DR GO; GO:0016926; P:protein desumoylation; IMP:UniProtKB.
DR GO; GO:0009154; P:purine ribonucleotide catabolic process; ISS:UniProtKB.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; ISS:UniProtKB.
DR Gene3D; 3.30.428.10; -; 1.
DR InterPro; IPR019808; Histidine_triad_CS.
DR InterPro; IPR001310; Histidine_triad_HIT.
DR InterPro; IPR011146; HIT-like.
DR InterPro; IPR036265; HIT-like_sf.
DR PANTHER; PTHR23089; PTHR23089; 1.
DR Pfam; PF01230; HIT; 1.
DR PRINTS; PR00332; HISTRIAD.
DR SUPFAM; SSF54197; SSF54197; 1.
DR PROSITE; PS00892; HIT_1; 1.
DR PROSITE; PS51084; HIT_2; 1.
PE 1: Evidence at protein level;
KW Acetylation; Apoptosis; Cytoplasm; Direct protein sequencing; Hydrolase;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Protease; Reference proteome;
KW Thiol protease; Transcription; Transcription regulation;
KW Ubl conjugation pathway.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:P62958"
FT CHAIN 2..126
FT /note="Adenosine 5'-monophosphoramidase HINT1"
FT /id="PRO_0000109782"
FT DOMAIN 18..126
FT /note="HIT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00464"
FT MOTIF 110..114
FT /note="Histidine triad motif"
FT ACT_SITE 112
FT /note="Tele-AMP-histidine intermediate"
FT /evidence="ECO:0000250|UniProtKB:P49773"
FT BINDING 43..44
FT /ligand="AMP"
FT /ligand_id="ChEBI:CHEBI:456215"
FT /evidence="ECO:0000250|UniProtKB:P49773"
FT BINDING 99
FT /ligand="AMP"
FT /ligand_id="ChEBI:CHEBI:456215"
FT /evidence="ECO:0000250|UniProtKB:P49773"
FT BINDING 105..107
FT /ligand="AMP"
FT /ligand_id="ChEBI:CHEBI:456215"
FT /evidence="ECO:0000250|UniProtKB:P49773"
FT BINDING 112..114
FT /ligand="AMP"
FT /ligand_id="ChEBI:CHEBI:456215"
FT /evidence="ECO:0000250|UniProtKB:P49773"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0000250|UniProtKB:P62958"
FT MOD_RES 21
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:23806337"
FT MOD_RES 30
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P49773"
FT MOD_RES 45
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 72
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MUTAGEN 17
FT /note="T->A: Loss of interaction with CALM1. No effect on
FT desumoylase activity."
FT /evidence="ECO:0000269|PubMed:31088288"
FT MUTAGEN 38
FT /note="C->S: No effect on desumoylase activity."
FT /evidence="ECO:0000269|PubMed:31088288"
FT MUTAGEN 84
FT /note="C->S: Loss of desumoylase activity."
FT /evidence="ECO:0000269|PubMed:31088288"
FT MUTAGEN 87
FT /note="D->V: Loss of desumoylase activity."
FT /evidence="ECO:0000269|PubMed:31088288"
FT MUTAGEN 112
FT /note="H->N: Reduced interaction with SUMO2."
FT /evidence="ECO:0000269|PubMed:31088288"
FT MUTAGEN 114
FT /note="H->R: Reduced interaction with SUMO2."
FT /evidence="ECO:0000269|PubMed:31088288"
FT MUTAGEN 115
FT /note="V->D: Significanly reduced interaction with SUMO2.
FT Loss of desumoylase activity."
FT /evidence="ECO:0000269|PubMed:31088288"
FT MUTAGEN 116
FT /note="L->Q: Significanly reduced interaction with SUMO2."
FT /evidence="ECO:0000269|PubMed:31088288"
SQ SEQUENCE 126 AA; 13777 MW; 30DA241476389805 CRC64;
MADEIAKAQV AQPGGDTIFG KIIRKEIPAK IIFEDDRCLA FHDISPQAPT HFLVIPKKHI
SQISVADDDD ESLLGHLMIV GKKCAADLGL KRGYRMVVNE GADGGQSVYH IHLHVLGGRQ
MNWPPG
