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O43316

- PAX4_HUMAN

UniProt

O43316 - PAX4_HUMAN

Protein

Paired box protein Pax-4

Gene

PAX4

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 142 (01 Oct 2014)
      Sequence version 1 (01 Jun 1998)
      Previous versions | rss
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    Functioni

    Plays an important role in the differentiation and development of pancreatic islet beta cells. Transcriptional repressor that binds to a common element in the glucagon, insulin and somatostatin promoters. Competes with PAX6 for this same promoter binding site. Isoform 2 appears to be a dominant negative form antagonizing PAX4 transcriptional activity.

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    DNA bindingi170 – 22960HomeoboxPROSITE-ProRule annotationAdd
    BLAST

    GO - Molecular functioni

    1. DNA binding Source: ProtInc
    2. double-stranded DNA binding Source: Ensembl
    3. sequence-specific DNA binding Source: InterPro
    4. sequence-specific DNA binding transcription factor activity Source: InterPro

    GO - Biological processi

    1. cell differentiation Source: UniProtKB-KW
    2. circadian rhythm Source: Ensembl
    3. endocrine pancreas development Source: Reactome
    4. negative regulation of apoptotic process Source: Ensembl
    5. negative regulation of transcription from RNA polymerase II promoter Source: Ensembl
    6. organ morphogenesis Source: ProtInc
    7. positive regulation of cell differentiation Source: Ensembl
    8. response to cAMP Source: Ensembl
    9. response to drug Source: Ensembl
    10. retina development in camera-type eye Source: Ensembl
    11. transcription, DNA-templated Source: UniProtKB-KW

    Keywords - Molecular functioni

    Developmental protein, Repressor

    Keywords - Biological processi

    Differentiation, Transcription, Transcription regulation

    Keywords - Ligandi

    DNA-binding

    Enzyme and pathway databases

    ReactomeiREACT_13650. Regulation of gene expression in endocrine-committed (NEUROG3+) progenitor cells.
    SignaLinkiO43316.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Paired box protein Pax-4
    Gene namesi
    Name:PAX4
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 7

    Organism-specific databases

    HGNCiHGNC:8618. PAX4.

    Subcellular locationi

    GO - Cellular componenti

    1. nucleoplasm Source: Reactome

    Keywords - Cellular componenti

    Nucleus

    Pathology & Biotechi

    Involvement in diseasei

    Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.
    Note: Disease susceptibility is associated with variations affecting the gene represented in this entry.
    Diabetes mellitus, insulin-dependent (IDDM) [MIM:222100]: A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical features are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.
    Note: Disease susceptibility is associated with variations affecting the gene represented in this entry.
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Isoform 3 (identifier: O43316-4)
    Natural varianti321 – 3211H → P Associated with susceptibility to IDDM.
    Corresponds to variant rs712701 [ dbSNP | Ensembl ].
    Diabetes mellitus, ketosis-prone (KPD) [MIM:612227]: An atypical form of diabetes mellitus characterized by an acute initial presentation with severe hyperglycemia and ketosis, as seen in classic type 1 diabetes, but after initiation of insulin therapy, prolonged remission is often possible with cessation of insulin therapy and maintenance of appropriate metabolic control. Metabolic studies show a markedly blunted insulin secretory response to glucose, partially reversible with the improvement of blood glucose control. Variable levels of insulin resistance are observed, especially in obese patients. Pancreatic beta-cell autoimmunity is a rare finding.
    Note: Disease susceptibility is associated with variations affecting the gene represented in this entry.
    Maturity-onset diabetes of the young 9 (MODY9) [MIM:612225]: A form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease.1 Publication
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti172 – 1721R → W in MODY9; the mutant sequence represses the activity of the insulin and glucagon promoters by only 35% compared to 50% and 57% respectively with wild-type sequence. 1 Publication
    VAR_054883

    Keywords - Diseasei

    Diabetes mellitus, Disease mutation

    Organism-specific databases

    MIMi125853. phenotype.
    222100. phenotype.
    612225. phenotype.
    612227. phenotype.
    Orphaneti552. MODY syndrome.
    PharmGKBiPA32958.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 350350Paired box protein Pax-4PRO_0000050180Add
    BLAST

    Proteomic databases

    PaxDbiO43316.
    PRIDEiO43316.

    Expressioni

    Gene expression databases

    ArrayExpressiO43316.
    BgeeiO43316.
    CleanExiHS_PAX4.
    GenevestigatoriO43316.

    Organism-specific databases

    HPAiHPA006806.
    HPA007182.

    Interactioni

    Protein-protein interaction databases

    STRINGi9606.ENSP00000339906.

    Structurei

    3D structure databases

    ProteinModelPortaliO43316.
    SMRiO43316. Positions 7-135, 164-243.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini5 – 131127PairedPROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni278 – 35073Transcription repressionAdd
    BLAST

    Sequence similaritiesi

    Belongs to the paired homeobox family.Curated
    Contains 1 homeobox DNA-binding domain.PROSITE-ProRule annotation
    Contains 1 paired domain.PROSITE-ProRule annotation

    Keywords - Domaini

    Homeobox, Paired box

    Phylogenomic databases

    eggNOGiNOG309473.
    HOGENOMiHOG000230939.
    HOVERGENiHBG009115.
    KOiK08032.
    OMAiESLGPSC.
    OrthoDBiEOG783MVM.
    PhylomeDBiO43316.
    TreeFamiTF320146.

    Family and domain databases

    Gene3Di1.10.10.10. 2 hits.
    1.10.10.60. 1 hit.
    InterProiIPR017970. Homeobox_CS.
    IPR001356. Homeobox_dom.
    IPR009057. Homeodomain-like.
    IPR001523. Paired_dom.
    IPR011991. WHTH_DNA-bd_dom.
    [Graphical view]
    PfamiPF00046. Homeobox. 1 hit.
    PF00292. PAX. 1 hit.
    [Graphical view]
    PRINTSiPR00027. PAIREDBOX.
    SMARTiSM00389. HOX. 1 hit.
    SM00351. PAX. 1 hit.
    [Graphical view]
    SUPFAMiSSF46689. SSF46689. 2 hits.
    PROSITEiPS00027. HOMEOBOX_1. 1 hit.
    PS50071. HOMEOBOX_2. 1 hit.
    PS00034. PAIRED_1. 1 hit.
    PS51057. PAIRED_2. 1 hit.
    [Graphical view]

    Sequences (3)i

    Sequence statusi: Complete.

    This entry describes 3 isoformsi produced by alternative splicing. Align

    Isoform 1 (identifier: O43316-1) [UniParc]FASTAAdd to Basket

    Also known as: Pax4

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide

    MHQDGISSMN QLGGLFVNGR PLPLDTRQQI VRLAVSGMRP CDISRILKVS    50
    NGCVSKILGR YYRTGVLEPK GIGGSKPRLA TPPVVARIAQ LKGECPALFA 100
    WEIQRQLCAE GLCTQDKTPS VSSINRVLRA LQEDQGLPCT RLRSPAVLAP 150
    AVLTPHSGSE TPRGTHPGTG HRNRTIFSPS QAEALEKEFQ RGQYPDSVAR 200
    GKLATATSLP EDTVRVWFSN RRAKWRRQEK LKWEMQLPGA SQGLTVPRVA 250
    PGIISAQQSP GSVPTAALPA LEPLGPSCYQ LCWATAPERC LSDTPPKACL 300
    KPCWDCGSFL LPVIAPSCVD VAWPCLDASL AHHLIGGAGK ATPTHFSHWP 350
    Length:350
    Mass (Da):37,833
    Last modified:June 1, 1998 - v1
    Checksum:i2C2343AF16AEAAAC
    GO
    Isoform 2 (identifier: O43316-2) [UniParc]FASTAAdd to Basket

    Also known as: Pax4V

    The sequence of this isoform differs from the canonical sequence as follows:
         239-257: Missing.
         258-350: QSPGSVPTAA...ATPTHFSHWP → AVPWQCAHSSPACPGTTGSLLLSAVLGNSTRKVSE

    Show »
    Length:273
    Mass (Da):29,820
    Checksum:i34658C1CBE7C81B5
    GO
    Isoform 3 (identifier: O43316-4) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-8: Missing.
         305-350: DCGSFLLPVI...ATPTHFSHWP → GHLPPQPNSL...PGCPLLYGLE

    Show »
    Length:343
    Mass (Da):37,061
    Checksum:iD58E65CD918472DA
    GO

    Sequence cautioni

    The sequence AC073934 differs from that shown. Reason: According to the human genome assembly there is a stop codon in position 349.

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti39 – 391R → Q.1 Publication
    Corresponds to variant rs115887120 [ dbSNP | Ensembl ].
    VAR_054879
    Natural varianti45 – 451R → W Associated with PKD susceptbility. 1 Publication
    VAR_054880
    Natural varianti129 – 1291R → W in diabetes mellitus type 2. 1 Publication
    Corresponds to variant rs114202595 [ dbSNP | Ensembl ].
    VAR_054881
    Natural varianti141 – 1411R → W Confers susceptibility to ketosis-prone diabetes mellitus. 1 Publication
    Corresponds to variant rs2233578 [ dbSNP | Ensembl ].
    VAR_054882
    Natural varianti172 – 1721R → W in MODY9; the mutant sequence represses the activity of the insulin and glucagon promoters by only 35% compared to 50% and 57% respectively with wild-type sequence. 1 Publication
    VAR_054883
    Natural varianti191 – 1911R → C.1 Publication
    Corresponds to variant rs114315130 [ dbSNP | Ensembl ].
    VAR_054884
    Natural varianti200 – 2001R → H.1 Publication
    Corresponds to variant rs2233580 [ dbSNP | Ensembl ].
    VAR_054885
    Natural varianti200 – 2001R → S.1 Publication
    Corresponds to variant rs3824004 [ dbSNP | Ensembl ].
    VAR_054886
    Isoform 3 (identifier: O43316-4)
    Natural varianti321 – 3211H → P Associated with susceptibility to IDDM.
    Corresponds to variant rs712701 [ dbSNP | Ensembl ].

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei1 – 88Missing in isoform 3. 2 PublicationsVSP_036448
    Alternative sequencei239 – 25719Missing in isoform 2. CuratedVSP_002359Add
    BLAST
    Alternative sequencei258 – 35093QSPGS…FSHWP → AVPWQCAHSSPACPGTTGSL LLSAVLGNSTRKVSE in isoform 2. CuratedVSP_002360Add
    BLAST
    Alternative sequencei305 – 35046DCGSF…FSHWP → GHLPPQPNSLDSGLLCLPCP SSHCHLASLSGSQALLWPGC PLLYGLE in isoform 3. 2 PublicationsVSP_036449Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AB008913 mRNA. Translation: BAA24506.1.
    AF043978 mRNA. Translation: AAD02289.1.
    AC073934 Genomic DNA. No translation available.
    BC074761 mRNA. Translation: AAH74761.1.
    CCDSiCCDS5797.1. [O43316-4]
    RefSeqiNP_006184.2. NM_006193.2. [O43316-4]
    UniGeneiHs.129706.

    Genome annotation databases

    EnsembliENST00000338516; ENSP00000344297; ENSG00000106331. [O43316-2]
    ENST00000341640; ENSP00000339906; ENSG00000106331. [O43316-4]
    GeneIDi5078.
    KEGGihsa:5078.
    UCSCiuc003vmg.1. human. [O43316-1]
    uc010lld.1. human. [O43316-4]

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AB008913 mRNA. Translation: BAA24506.1 .
    AF043978 mRNA. Translation: AAD02289.1 .
    AC073934 Genomic DNA. No translation available.
    BC074761 mRNA. Translation: AAH74761.1 .
    CCDSi CCDS5797.1. [O43316-4 ]
    RefSeqi NP_006184.2. NM_006193.2. [O43316-4 ]
    UniGenei Hs.129706.

    3D structure databases

    ProteinModelPortali O43316.
    SMRi O43316. Positions 7-135, 164-243.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    STRINGi 9606.ENSP00000339906.

    Proteomic databases

    PaxDbi O43316.
    PRIDEi O43316.

    Protocols and materials databases

    DNASUi 5078.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000338516 ; ENSP00000344297 ; ENSG00000106331 . [O43316-2 ]
    ENST00000341640 ; ENSP00000339906 ; ENSG00000106331 . [O43316-4 ]
    GeneIDi 5078.
    KEGGi hsa:5078.
    UCSCi uc003vmg.1. human. [O43316-1 ]
    uc010lld.1. human. [O43316-4 ]

    Organism-specific databases

    CTDi 5078.
    GeneCardsi GC07M127250.
    H-InvDB HIX0033508.
    HGNCi HGNC:8618. PAX4.
    HPAi HPA006806.
    HPA007182.
    MIMi 125853. phenotype.
    167413. gene.
    222100. phenotype.
    612225. phenotype.
    612227. phenotype.
    neXtProti NX_O43316.
    Orphaneti 552. MODY syndrome.
    PharmGKBi PA32958.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi NOG309473.
    HOGENOMi HOG000230939.
    HOVERGENi HBG009115.
    KOi K08032.
    OMAi ESLGPSC.
    OrthoDBi EOG783MVM.
    PhylomeDBi O43316.
    TreeFami TF320146.

    Enzyme and pathway databases

    Reactomei REACT_13650. Regulation of gene expression in endocrine-committed (NEUROG3+) progenitor cells.
    SignaLinki O43316.

    Miscellaneous databases

    GeneWikii PAX4.
    GenomeRNAii 5078.
    NextBioi 19588.
    PROi O43316.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi O43316.
    Bgeei O43316.
    CleanExi HS_PAX4.
    Genevestigatori O43316.

    Family and domain databases

    Gene3Di 1.10.10.10. 2 hits.
    1.10.10.60. 1 hit.
    InterProi IPR017970. Homeobox_CS.
    IPR001356. Homeobox_dom.
    IPR009057. Homeodomain-like.
    IPR001523. Paired_dom.
    IPR011991. WHTH_DNA-bd_dom.
    [Graphical view ]
    Pfami PF00046. Homeobox. 1 hit.
    PF00292. PAX. 1 hit.
    [Graphical view ]
    PRINTSi PR00027. PAIREDBOX.
    SMARTi SM00389. HOX. 1 hit.
    SM00351. PAX. 1 hit.
    [Graphical view ]
    SUPFAMi SSF46689. SSF46689. 2 hits.
    PROSITEi PS00027. HOMEOBOX_1. 1 hit.
    PS50071. HOMEOBOX_2. 1 hit.
    PS00034. PAIRED_1. 1 hit.
    PS51057. PAIRED_2. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Molecular cloning of mouse paired-box-containing gene (Pax-4) from an islet beta cell line and deduced sequence of human Pax-4."
      Matsushita T., Yamaoka T., Otsuka S., Moritani M., Matsumoto T., Itakura M.
      Biochem. Biophys. Res. Commun. 242:176-180(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
    2. Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
      Tissue: Placenta.
    3. "The DNA sequence of human chromosome 7."
      Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H., Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A., Delehaunty K.D., Miner T.L.
      , Nash W.E., Cordes M., Du H., Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C., Latreille P., Miller N., Johnson D., Murray J., Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E., Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H., Wilson R.K.
      Nature 424:157-164(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    4. "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] (ISOFORM 3).
      Tissue: Colon.
    5. Cited for: ALTERNATIVE SPLICING (ISOFORM 2).
      Tissue: Insulinoma.
    6. "A missense mutation of Pax4 gene (R121W) is associated with type 2 diabetes in Japanese."
      Shimajiri Y., Sanke T., Furuta H., Hanabusa T., Nakagawa T., Fujitani Y., Kajimoto Y., Takasu N., Nanjo K.
      Diabetes 50:2864-2869(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANT DIABETES MELLITUS TYPE 2 TRP-129.
    7. Cited for: VARIANTS TRP-45 AND TRP-141, ASSOCIATION WITH SUSCEPTIBILITY TO KETOSIS-PRONE DIABETES.
    8. "Association of childhood type 1 diabetes mellitus with a variant of PAX4: possible link to beta cell regenerative capacity."
      Biason-Lauber A., Boehm B., Lang-Muritano M., Gauthier B.R., Brun T., Wollheim C.B., Schoenle E.J.
      Diabetologia 48:900-905(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANT PRO-321 (ISOFORM 3), ASSOCIATION WITH SUSCEPTIBILITY TO IDDM.
    9. Cited for: VARIANT MODY9 TRP-172, VARIANTS GLN-39; CYS-191; HIS-200 AND SER-200, VARIANT PRO-321 (ISOFORM 3), CHARACTERIZATION OF VARIANT MODY9 TRP-172.

    Entry informationi

    Entry nameiPAX4_HUMAN
    AccessioniPrimary (citable) accession number: O43316
    Secondary accession number(s): O95161, Q6B0H0
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: December 15, 1998
    Last sequence update: June 1, 1998
    Last modified: October 1, 2014
    This is version 142 of the entry and version 1 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

    Complete proteome, Reference proteome

    Documents

    1. Human chromosome 7
      Human chromosome 7: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3