Biology:Insulin-induced gene 1 protein

Generic protein structure example

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

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:

• Niemann-Pick disease type C1 protein, which participates in the intracellular movement of cholesterol
• Patched, the receptor for Hedgehog, a protein that contains covalently bound cholesterol

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.

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.

Further reading

• "Cloning, human chromosomal assignment, and adipose and hepatic expression of the CL-6/INSIG1 gene". Genomics 43 (3): 278–84. Aug 1997. doi:10.1006/geno.1997.4821. PMID 9268630. 
• "Reduced expression of the insulin-induced protein 1 and p41 Arp2/3 complex genes in human gastric cancers". International Journal of Cancer 100 (1): 57–62. Jul 2002. doi:10.1002/ijc.10464. PMID 12115587. 
• "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. Aug 2002. doi:10.1016/S0092-8674(02)00872-3. PMID 12202038. 
• "Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins". Proceedings of the National Academy of Sciences of the United States of America 99 (20): 12753–8. Oct 2002. doi:10.1073/pnas.162488899. PMID 12242332. 
• "The hypocholesterolemic agent LY295427 up-regulates INSIG-1, identifying the INSIG-1 protein as a mediator of cholesterol homeostasis through SREBP". Proceedings of the National Academy of Sciences of the United States of America 99 (20): 12675–80. Oct 2002. doi:10.1073/pnas.202471599. PMID 12242342. 
• "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proceedings of the National Academy of Sciences of the United States of America 99 (26): 16899–903. Dec 2002. doi:10.1073/pnas.242603899. PMID 12477932. 
• "Three mutations in sterol-sensing domain of SCAP block interaction with insig and render SREBP cleavage insensitive to sterols". Proceedings of the National Academy of Sciences of the United States of America 99 (26): 16672–7. Dec 2002. doi:10.1073/pnas.262669399. PMID 12482938. 
• "Accelerated degradation of HMG CoA reductase mediated by binding of insig-1 to its sterol-sensing domain". Molecular Cell 11 (1): 25–33. Jan 2003. doi:10.1016/S1097-2765(02)00822-5. PMID 12535518. 
• "Human chromosome 7: DNA sequence and biology". Science 300 (5620): 767–72. May 2003. doi:10.1126/science.1083423. PMID 12690205. 
• "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. Sep 2003. doi:10.1074/jbc.M306476200. PMID 12842885. 
• "Insig-1 "brakes" lipogenesis in adipocytes and inhibits differentiation of preadipocytes". Proceedings of the National Academy of Sciences of the United States of America 100 (16): 9476–81. Aug 2003. doi:10.1073/pnas.1133426100. PMID 12869692. 
• "Cholesterol-induced conformational change in SCAP enhanced by Insig proteins and mimicked by cationic amphiphiles". Proceedings of the National Academy of Sciences of the United States of America 100 (19): 10647–52. Sep 2003. doi:10.1073/pnas.1534833100. PMID 12963821. 
• "Membrane topology of human insig-1, a protein regulator of lipid synthesis". The Journal of Biological Chemistry 279 (9): 8487–96. Feb 2004. doi:10.1074/jbc.M312623200. PMID 14660594. 
• "Overexpression of Insig-1 in the livers of transgenic mice inhibits SREBP processing and reduces insulin-stimulated lipogenesis". The Journal of Clinical Investigation 113 (8): 1168–75. Apr 2004. doi:10.1172/JCI20978. PMID 15085196. 
• "Isolation of mutant cells lacking Insig-1 through selection with SR-12813, an agent that stimulates degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase". The Journal of Biological Chemistry 279 (41): 43136–47. Oct 2004. doi:10.1074/jbc.M406406200. PMID 15247248. 
• "Proteolytic activation of sterol regulatory element-binding protein induced by cellular stress through depletion of Insig-1". The Journal of Biological Chemistry 279 (43): 45257–65. Oct 2004. doi:10.1074/jbc.M408235200. PMID 15304479. 
• "Photo-leucine and photo-methionine allow identification of protein-protein interactions in living cells". Nature Methods 2 (4): 261–7. Apr 2005. doi:10.1038/nmeth752. PMID 15782218. 
• "Insig required for sterol-mediated inhibition of Scap/SREBP binding to COPII proteins in vitro". The Journal of Biological Chemistry 280 (28): 26483–90. Jul 2005. doi:10.1074/jbc.M504041200. PMID 15899885. 

External links

• Uniprot description of INSIG1
• Bioinformatic Harvester entry of INSIG1