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Protein

Insulinoma-associated protein 1

Gene

INSM1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Sequence-specific DNA-binding transcriptional regulator that plays a key role in neurogenesis and neuroendocrine cell differentiation during embryonic and/or fetal development. Binds to the consensus sequence 5'-[TG][TC][TC][TT][GA]GGG[CG]A-3' in target promoters. Acts as a transcriptional repressor of NEUROD1 and INS expression via its interaction with cyclin CCND1 in a cell cycle-independent manner. Negatively regulates skeletal muscle-specific gene expression in endocrine cells of the pituitary by inhibiting the Notch signaling pathway. Represses target gene transcription by recruiting chromatin-modifying factors, such as HDAC1, HDAC2, HDAC3, KDM1A and RCOR1 histone deacetylases. Binds to its own promoter, suggesting autoregulation as a self-control feedback mechanism. Promotes the generation and expansion of neuronal basal progenitor cells in the developing neocortex. Involved in the differentiation of endocrine cells of the developing anterior pituitary gland, of the pancreas and intestine, and of sympatho-adrenal cells in the peripheral nervous system. Promotes cell cycle signaling arrest and inhibition of cellular proliferation.5 Publications

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Zinc fingeri267 – 28721C2H2-type 1; atypicalPROSITE-ProRule annotationAdd
BLAST
Zinc fingeri295 – 31723C2H2-type 2PROSITE-ProRule annotationAdd
BLAST
Zinc fingeri367 – 38923C2H2-type 3PROSITE-ProRule annotationAdd
BLAST
Zinc fingeri441 – 46424C2H2-type 4PROSITE-ProRule annotationAdd
BLAST
Zinc fingeri469 – 49224C2H2-type 5PROSITE-ProRule annotationAdd
BLAST

GO - Molecular functioni

  1. chromatin DNA binding Source: UniProtKB
  2. core promoter binding Source: UniProtKB
  3. cyclin binding Source: UniProtKB
  4. histone deacetylase binding Source: UniProtKB
  5. metal ion binding Source: UniProtKB-KW
  6. RNA polymerase II core promoter proximal region sequence-specific DNA binding Source: NTNU_SB
  7. RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in negative regulation of transcription Source: NTNU_SB
  8. sequence-specific DNA binding transcription factor activity Source: UniProtKB

GO - Biological processi

  1. adrenal chromaffin cell differentiation Source: UniProtKB
  2. cell cycle Source: UniProtKB-KW
  3. endocrine pancreas development Source: Reactome
  4. negative regulation of cell proliferation Source: UniProtKB
  5. negative regulation of protein phosphorylation Source: UniProtKB
  6. negative regulation of transcription from RNA polymerase II promoter Source: UniProtKB
  7. noradrenergic neuron development Source: UniProtKB
  8. norepinephrine biosynthetic process Source: UniProtKB
  9. pancreatic A cell differentiation Source: UniProtKB
  10. positive regulation of cell cycle arrest Source: UniProtKB
  11. positive regulation of cell differentiation Source: UniProtKB
  12. positive regulation of neural precursor cell proliferation Source: UniProtKB
  13. regulation of gene expression Source: UniProtKB
  14. regulation of protein complex assembly Source: UniProtKB
  15. sympathetic ganglion development Source: UniProtKB
  16. transdifferentiation Source: UniProtKB
  17. type B pancreatic cell development Source: Ensembl
  18. type B pancreatic cell differentiation Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Developmental protein, Repressor

Keywords - Biological processi

Cell cycle, Differentiation, Neurogenesis, Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding, Metal-binding, Zinc

Enzyme and pathway databases

ReactomeiREACT_13650. Regulation of gene expression in endocrine-committed (NEUROG3+) progenitor cells.
SignaLinkiQ01101.

Names & Taxonomyi

Protein namesi
Recommended name:
Insulinoma-associated protein 1
Alternative name(s):
Zinc finger protein IA-1
Gene namesi
Name:INSM1
Synonyms:IA1
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640 Componenti: Chromosome 20

Organism-specific databases

HGNCiHGNC:6090. INSM1.

Subcellular locationi

  1. Nucleus By similarity

GO - Cellular componenti

  1. nucleoplasm Source: Reactome
  2. nucleus Source: UniProtKB
  3. transcriptional repressor complex Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi43 – 5816PPAPS…PPPPP → LLALSLVLGLLLLLLL: Inhibits weakly translational repression activity. Inhibits interaction with CCND1 and cell cycle arrest. 1 PublicationAdd
BLAST

Organism-specific databases

PharmGKBiPA29897.

Polymorphism and mutation databases

BioMutaiINSM1.
DMDMi547700.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 510510Insulinoma-associated protein 1PRO_0000047268Add
BLAST

Proteomic databases

PaxDbiQ01101.
PRIDEiQ01101.

PTM databases

PhosphoSiteiQ01101.

Expressioni

Tissue specificityi

Expressed in pancreatic duct cells. Expressed in several tumor cell lines of neuroendocrine origin including pheochromocytoma, medullary thyroid carcinoma, insulinoma, medulloblastoma, retinoblastoma, pheochromacytoma, medullary thyroid carcinoma and small cell lung carcinoma.2 Publications

Inductioni

Up-regulated by transcription factors, such as MASH1, NEUROD1, NEUROG3, NGN3 and TCF3.2 Publications

Gene expression databases

BgeeiQ01101.
CleanExiHS_INSM1.
GenevestigatoriQ01101.

Interactioni

Subunit structurei

Interacts (via the SNAG domain) with HDAC1. Interacts (via the SNAG domain) with HDAC2. Interacts (via the SNAG domain) with KDM1A. Interacts (via the SNAG domain) with RCOR1. Interacts with SORBS1 (By similarity). Interacts (via the N-terminal region) with CCND1 (via cyclin N-terminal domain); the interaction competes with the binding of CCND1 to CDK4 during cell cycle progression and increases its transcriptional repressor activity. Interacts with HDAC3; the interaction increases its transcriptional repressor activity. Interacts with HDAC1.By similarity4 Publications

Protein-protein interaction databases

BioGridi109853. 5 interactions.
IntActiQ01101. 5 interactions.
MINTiMINT-1395936.
STRINGi9606.ENSP00000312631.

Structurei

Secondary structure

1
510
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Helixi3 – 53Combined sources
Beta strandi449 – 4524Combined sources
Helixi453 – 4619Combined sources
Beta strandi466 – 4705Combined sources
Beta strandi477 – 4804Combined sources
Helixi481 – 4899Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
2LV2NMR-A424-497[»]
3ZMSX-ray2.96C2-510[»]
ProteinModelPortaliQ01101.
SMRiQ01101. Positions 215-497.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni1 – 2020SNAG domainBy similarityAdd
BLAST
Regioni43 – 5816Necessary for interaction with CCND1Add
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi1 – 250250Ala/Gly/Pro-richAdd
BLAST

Domaini

The C-terminal region is necessary for NEUROD1 promoter DNA-binding and transcriptional repressor activity.

Sequence similaritiesi

Belongs to the INSM1 family.Curated
Contains 5 C2H2-type zinc fingers.PROSITE-ProRule annotation

Zinc finger

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Zinc fingeri267 – 28721C2H2-type 1; atypicalPROSITE-ProRule annotationAdd
BLAST
Zinc fingeri295 – 31723C2H2-type 2PROSITE-ProRule annotationAdd
BLAST
Zinc fingeri367 – 38923C2H2-type 3PROSITE-ProRule annotationAdd
BLAST
Zinc fingeri441 – 46424C2H2-type 4PROSITE-ProRule annotationAdd
BLAST
Zinc fingeri469 – 49224C2H2-type 5PROSITE-ProRule annotationAdd
BLAST

Keywords - Domaini

Repeat, Zinc-finger

Phylogenomic databases

eggNOGiNOG308747.
GeneTreeiENSGT00530000064190.
HOGENOMiHOG000113079.
HOVERGENiHBG052137.
InParanoidiQ01101.
OMAiREHEKHK.
OrthoDBiEOG7JMGDD.
PhylomeDBiQ01101.
TreeFamiTF320538.

Family and domain databases

Gene3Di3.30.160.60. 1 hit.
InterProiIPR007087. Znf_C2H2.
IPR015880. Znf_C2H2-like.
IPR013087. Znf_C2H2/integrase_DNA-bd.
[Graphical view]
PfamiPF00096. zf-C2H2. 4 hits.
[Graphical view]
SMARTiSM00355. ZnF_C2H2. 5 hits.
[Graphical view]
PROSITEiPS00028. ZINC_FINGER_C2H2_1. 4 hits.
PS50157. ZINC_FINGER_C2H2_2. 4 hits.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q01101-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MPRGFLVKRS KKSTPVSYRV RGGEDGDRAL LLSPSCGGAR AEPPAPSPVP
60 70 80 90 100
GPLPPPPPAE RAHAALAAAL ACAPGPQPPP QGPRAAHFGN PEAAHPAPLY
110 120 130 140 150
SPTRPVSREH EKHKYFERSF NLGSPVSAES FPTPAALLGG GGGGGASGAG
160 170 180 190 200
GGGTCGGDPL LFAPAELKMG TAFSAGAEAA RGPGPGPPLP PAAALRPPGK
210 220 230 240 250
RPPPPTAAEP PAKAVKAPGA KKPKAIRKLH FEDEVTTSPV LGLKIKEGPV
260 270 280 290 300
EAPRGRAGGA ARPLGEFICQ LCKEEYADPF ALAQHKCSRI VRVEYRCPEC
310 320 330 340 350
AKVFSCPANL ASHRRWHKPR PAPAAARAPE PEAAARAEAR EAPGGGSDRD
360 370 380 390 400
TPSPGGVSES GSEDGLYECH HCAKKFRRQA YLRKHLLAHH QALQAKGAPL
410 420 430 440 450
APPAEDLLAL YPGPDEKAPQ EAAGDGEGAG VLGLSASAEC HLCPVCGESF
460 470 480 490 500
ASKGAQERHL RLLHAAQVFP CKYCPATFYS SPGLTRHINK CHPSENRQVI
510
LLQVPVRPAC
Length:510
Mass (Da):52,923
Last modified:June 1, 1994 - v1
Checksum:i22D4E97696397365
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M93119 mRNA. Translation: AAA58680.1.
AL161658 Genomic DNA. Translation: CAC36065.1.
U07172 Genomic DNA. Translation: AAA20938.1.
CCDSiCCDS13143.1.
PIRiA42750.
RefSeqiNP_002187.1. NM_002196.2.
UniGeneiHs.89584.

Genome annotation databases

EnsembliENST00000310227; ENSP00000312631; ENSG00000173404.
GeneIDi3642.
KEGGihsa:3642.
UCSCiuc002wrx.3. human.

Polymorphism and mutation databases

BioMutaiINSM1.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M93119 mRNA. Translation: AAA58680.1.
AL161658 Genomic DNA. Translation: CAC36065.1.
U07172 Genomic DNA. Translation: AAA20938.1.
CCDSiCCDS13143.1.
PIRiA42750.
RefSeqiNP_002187.1. NM_002196.2.
UniGeneiHs.89584.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
2LV2NMR-A424-497[»]
3ZMSX-ray2.96C2-510[»]
ProteinModelPortaliQ01101.
SMRiQ01101. Positions 215-497.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi109853. 5 interactions.
IntActiQ01101. 5 interactions.
MINTiMINT-1395936.
STRINGi9606.ENSP00000312631.

PTM databases

PhosphoSiteiQ01101.

Polymorphism and mutation databases

BioMutaiINSM1.
DMDMi547700.

Proteomic databases

PaxDbiQ01101.
PRIDEiQ01101.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000310227; ENSP00000312631; ENSG00000173404.
GeneIDi3642.
KEGGihsa:3642.
UCSCiuc002wrx.3. human.

Organism-specific databases

CTDi3642.
GeneCardsiGC20P020348.
HGNCiHGNC:6090. INSM1.
MIMi600010. gene.
neXtProtiNX_Q01101.
PharmGKBiPA29897.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiNOG308747.
GeneTreeiENSGT00530000064190.
HOGENOMiHOG000113079.
HOVERGENiHBG052137.
InParanoidiQ01101.
OMAiREHEKHK.
OrthoDBiEOG7JMGDD.
PhylomeDBiQ01101.
TreeFamiTF320538.

Enzyme and pathway databases

ReactomeiREACT_13650. Regulation of gene expression in endocrine-committed (NEUROG3+) progenitor cells.
SignaLinkiQ01101.

Miscellaneous databases

GeneWikiiINSM1.
GenomeRNAii3642.
NextBioi14255.
PROiQ01101.
SOURCEiSearch...

Gene expression databases

BgeeiQ01101.
CleanExiHS_INSM1.
GenevestigatoriQ01101.

Family and domain databases

Gene3Di3.30.160.60. 1 hit.
InterProiIPR007087. Znf_C2H2.
IPR015880. Znf_C2H2-like.
IPR013087. Znf_C2H2/integrase_DNA-bd.
[Graphical view]
PfamiPF00096. zf-C2H2. 4 hits.
[Graphical view]
SMARTiSM00355. ZnF_C2H2. 5 hits.
[Graphical view]
PROSITEiPS00028. ZINC_FINGER_C2H2_1. 4 hits.
PS50157. ZINC_FINGER_C2H2_2. 4 hits.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "A novel human insulinoma-associated cDNA, IA-1, encodes a protein with 'zinc-finger' DNA-binding motifs."
    Goto Y., de Silva M.G., Toscani A., Prabhakar B.S., Notkins A.L., Lan M.S.
    J. Biol. Chem. 267:15252-15257(1992) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY.
  2. "The DNA sequence and comparative analysis of human chromosome 20."
    Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P., Bird C.P., Blakey S.E.
    , Bridgeman A.M., Brown A.J., Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J.
    Nature 414:865-871(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  3. "Genomic organization, 5'-upstream sequence, and chromosomal localization of an insulinoma-associated intronless gene, IA-1."
    Lan M.S., Li Q., Lu J., Modi W.S., Notkins A.L.
    J. Biol. Chem. 269:14170-14174(1994) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-11.
  4. "Neuroendocrine differentiation factor, IA-1, is a transcriptional repressor and contains a specific DNA-binding domain: identification of consensus IA-1 binding sequence."
    Breslin M.B., Zhu M., Notkins A.L., Lan M.S.
    Nucleic Acids Res. 30:1038-1045(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, DNA-BINDING.
  5. "NeuroD1/E47 regulates the E-box element of a novel zinc finger transcription factor, IA-1, in developing nervous system."
    Breslin M.B., Zhu M., Lan M.S.
    J. Biol. Chem. 278:38991-38997(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: INDUCTION, TISSUE SPECIFICITY.
  6. "INSM1 functions as a transcriptional repressor of the neuroD/beta2 gene through the recruitment of cyclin D1 and histone deacetylases."
    Liu W.D., Wang H.W., Muguira M., Breslin M.B., Lan M.S.
    Biochem. J. 397:169-177(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, DNA-BINDING, INTERACTION WITH CCND1; HDAC1 AND HDAC3.
  7. Cited for: FUNCTION, INDUCTION.
  8. "Identification of an INSM1-binding site in the insulin promoter: negative regulation of the insulin gene transcription."
    Wang H.W., Muguira M., Liu W.D., Zhang T., Chen C., Aucoin R., Breslin M.B., Lan M.S.
    J. Endocrinol. 198:29-39(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, DNA-BINDING, INTERACTION WITH CCND1 AND HDAC3.
  9. "Zinc finger transcription factor INSM1 interrupts cyclin D1 and CDK4 binding and induces cell cycle arrest."
    Zhang T., Liu W.D., Saunee N.A., Breslin M.B., Lan M.S.
    J. Biol. Chem. 284:5574-5581(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, DNA-BINDING, INTERACTION WITH CCND1, MUTAGENESIS OF 43-PRO--PRO-58.
  10. "Structure, expression, and biological function of INSM1 transcription factor in neuroendocrine differentiation."
    Lan M.S., Breslin M.B.
    FASEB J. 23:2024-2033(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: REVIEW.
  11. "Solution NMR structure of C2H2-type zinc-fingers 4 and 5 from human insulinoma-associated protein 1 (fragment 424-497), Northeast structural genomics consortium target HR7614B (Casp target)."
    Northeast structural genomics consortium (NESG)
    Submitted (OCT-2012) to the PDB data bank
    Cited for: STRUCTURE BY NMR OF 424-497 IN COMPLEX WITH ZINC IONS.

Entry informationi

Entry nameiINSM1_HUMAN
AccessioniPrimary (citable) accession number: Q01101
Entry historyi
Integrated into UniProtKB/Swiss-Prot: June 1, 1994
Last sequence update: June 1, 1994
Last modified: April 29, 2015
This is version 128 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

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 20
    Human chromosome 20: 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
  4. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.