Insulin-induced gene 1 protein

Insulin induced gene 1, also known as INSIG1, is a protein which in humans is encoded by the INSIG1 gene.[5][6]

INSIG1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesINSIG1, CL-6, CL6, insulin induced gene 1
External IDsOMIM: 602055 MGI: 1916289 HomoloGene: 4047 GeneCards: INSIG1
Orthologs
SpeciesHumanMouse
Entrez

3638

231070

Ensembl

ENSG00000186480

ENSMUSG00000045294

UniProt

O15503

Q8BGI3

RefSeq (mRNA)

NM_153526

RefSeq (protein)

NP_705746

Location (UCSC)Chr 7: 155.3 – 155.31 MbChr 5: 28.28 – 28.28 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

INSIG1 is short for insulin-induced gene 1; it is located on chromosome 7 (7q36). This human gene encodes for a transmembrane protein of 277 amino acids with probably 6 transmembrane domains. It is localized in the endoplasmic reticulum (ER) and seems to be expressed in all tissues, especially in liver. This gene is called an insulin-induced gene because the molecule insulin can regulate it. Importantly, the protein encoded by this gene plays a critical role in regulating cholesterol concentrations in cells.

Function

  1. INSIG1 plays an important role in the SREBP-mediated regulation of cholesterol biosynthesis: by binding to the sterol-sensing domain of SCAP (SREBP cleavage activating protein) it makes the SCAP/SREBP complex stay longer in the ER, thus prohibiting SCAP from carrying activated SREBP to the golgi complex. This ultimately blocks SREBP from acting as a transcription factor for the SRE in the promoter region of the HMG-CoA-reductase gene and results in a decreased expression of HMG-CoA-reductase.
  2. INSIG1 also binds to the sterol-sensing domain of HMG-CoA-reductase, resulting in the enzyme's increased degradation.

Both functions require the binding of INSIG1 protein via the same site.

There are two other proteins whose sterol-binding sites show a great similarity to the ones of SCAP and HMG-CoA-reductase and who might thus be regulated by INSIG1 as well:

Oxysterols regulate cholesterol homeostasis through liver X receptor (LXR) and sterol regulatory element-binding protein (SREBP) mediated signaling pathway. This protein binds to the sterol-sensing domains of SREBP cleavage-activating protein (SCAP) and HMG CoA reductase, and is essential for the sterol-mediated trafficking of the two proteins. Alternatively spliced transcript variants encoding distinct isoforms have been observed.[6]

Regulation

INSIG1 is regulated by insulin and highly expressed in liver.

Sequence (277 AA)

MPRLHDHFWS CSCAHSARRR GPPRASTAGL PPKVGEMINV SVSGPSLLAA HGAPDADPAP RGRSAAMSGP EPGSPYPNTW HHRLLQRSLV LFSVGVVLAL VLNLLQIQRN VTLFPEEVIA TIFSSAWWVP PCCGTAAAVV GLLYPCIDSH LGEPHKFKRE WASVMRCIAV FVGINHASAK LDFANNVQLS LTLAALSLGL WWTFDRSRSG LGLGITIAFL ATLITQFLVY NGVYQYTSPD FLYIRSWLPC IFFSGGVTVG NIGRQLAMGV PEKPHSD

Synonyms

CL-6, INSIG-1, Insulin-induced gene 1 protein, MGC1405 (source: iHOP)

Interactions

INSIG1 has been shown to interact with SREBF2.[7][8]

References

  1. GRCh38: Ensembl release 89: ENSG00000186480 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000045294 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Peng Y, Schwarz EJ, Lazar MA, Genin A, Spinner NB, Taub R (Aug 1997). "Cloning, human chromosomal assignment, and adipose and hepatic expression of the CL-6/INSIG1 gene". Genomics. 43 (3): 278–84. doi:10.1006/geno.1997.4821. PMID 9268630.
  6. "Entrez Gene: INSIG1 insulin induced gene 1".
  7. Dobrosotskaya IY, Goldstein JL, Brown MS, Rawson RB (Sep 2003). "Reconstitution of sterol-regulated endoplasmic reticulum-to-Golgi transport of SREBP-2 in insect cells by co-expression of mammalian SCAP and Insigs". The Journal of Biological Chemistry. 278 (37): 35837–43. doi:10.1074/jbc.M306476200. PMID 12842885.
  8. Yang T, Espenshade PJ, Wright ME, Yabe D, Gong Y, Aebersold R, Goldstein JL, Brown MS (Aug 2002). "Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER". Cell. 110 (4): 489–500. doi:10.1016/S0092-8674(02)00872-3. PMID 12202038. S2CID 15052132.

Further reading

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