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O43316

- PAX4_HUMAN

UniProt

O43316 - PAX4_HUMAN

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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

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. RNA polymerase II distal enhancer sequence-specific DNA binding Source: Ensembl
  4. RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity involved in negative regulation of transcription Source: Ensembl

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. organ morphogenesis Source: ProtInc
  6. positive regulation of cell differentiation Source: Ensembl
  7. response to cAMP Source: Ensembl
  8. response to drug Source: Ensembl
  9. retina development in camera-type eye Source: Ensembl
Complete GO annotation...

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
Complete GO annotation...

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

BgeeiO43316.
CleanExiHS_PAX4.
ExpressionAtlasiO43316. baseline.
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.
GeneTreeiENSGT00680000099553.
HOGENOMiHOG000230939.
HOVERGENiHBG009115.
InParanoidiO43316.
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

        10         20         30         40         50
MHQDGISSMN QLGGLFVNGR PLPLDTRQQI VRLAVSGMRP CDISRILKVS
60 70 80 90 100
NGCVSKILGR YYRTGVLEPK GIGGSKPRLA TPPVVARIAQ LKGECPALFA
110 120 130 140 150
WEIQRQLCAE GLCTQDKTPS VSSINRVLRA LQEDQGLPCT RLRSPAVLAP
160 170 180 190 200
AVLTPHSGSE TPRGTHPGTG HRNRTIFSPS QAEALEKEFQ RGQYPDSVAR
210 220 230 240 250
GKLATATSLP EDTVRVWFSN RRAKWRRQEK LKWEMQLPGA SQGLTVPRVA
260 270 280 290 300
PGIISAQQSP GSVPTAALPA LEPLGPSCYQ LCWATAPERC LSDTPPKACL
310 320 330 340 350
KPCWDCGSFL LPVIAPSCVD VAWPCLDASL AHHLIGGAGK ATPTHFSHWP
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

EnsembliENST00000341640; 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 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.
GeneTreei ENSGT00680000099553.
HOGENOMi HOG000230939.
HOVERGENi HBG009115.
InParanoidi O43316.
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

Bgeei O43316.
CleanExi HS_PAX4.
ExpressionAtlasi O43316. baseline.
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

« Hide 'large scale' publications
  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 29, 2014
This is version 143 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