Insulin induced gene 1, also known as INSIG1, is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
which in humans is encoded by the ''INSIG1''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
''INSIG1'' is short for
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...
-induced
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
1; it is located on
chromosome 7
Chromosome 7 is one of the 23 pairs of chromosomes in humans, who normally have two copies of this chromosome. Chromosome 7 spans about 160 million base pairs (the building material of DNA) and represents between 5 and 5.5 percent of the total DN ...
(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
The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...
(ER) and seems to be expressed in all tissues, especially in
liver
The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
. This gene is called an
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...
-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
#INSIG1 plays an important role in the
SREBP
Sterol regulatory element-binding proteins (SREBPs) are transcription factors that bind to the sterol regulatory element DNA sequence TCACNCCAC. Mammalian SREBPs are encoded by the genes '' SREBF1'' and '' SREBF2''. SREBPs belong to the basic- ...
-mediated regulation of
cholesterol
Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils.
Cholesterol is biosynthesis, biosynthesized by all anima ...
biosynthesis: by binding to the
sterol-sensing domain A sterol-sensing domain (SSD) is a protein domain which consists of 180 amino acids forming five transmembrane segments capable of binding sterol groups. This type of domain is present in proteins involved in cholesterol metabolism and signalling.
...
of
SCAP
SCAP may refer to:
* S.C.A.P., an early French manufacturer of cars and engines
* Security Content Automation Protocol
* '' The Shackled City Adventure Path'', a role-playing game
* SREBP cleavage activating protein
* Supervisory Capital Assessm ...
(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
The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic Cell (biology), cells. Part of the endomembrane system in the cytoplasm, it protein targeting, packages proteins ...
. 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.
#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
Patched (Ptc) is a conserved 12-pass transmembrane protein receptor that plays an obligate negative regulatory role in the Hedgehog signaling pathway in insects and vertebrates. Patched is an essential gene in embryogenesis for proper segme ...
, the receptor for Hedgehog, a protein that contains covalently bound cholesterol
Oxysterol
An oxysterol is a derivative of cholesterol obtained by Redox, oxidation involving enzymes and / or pro-oxidants. Such compounds play important roles in various biological processes such as cholesterol homeostasis, lipid metabolism (sphingolipids, ...
s regulate cholesterol homeostasis through liver X receptor (
LXR) and sterol regulatory element-binding protein (
SREBP
Sterol regulatory element-binding proteins (SREBPs) are transcription factors that bind to the sterol regulatory element DNA sequence TCACNCCAC. Mammalian SREBPs are encoded by the genes '' SREBF1'' and '' SREBF2''. SREBPs belong to the basic- ...
) mediated signaling pathway. This protein binds to the sterol-sensing domains of SREBP cleavage-activating protein (
SCAP
SCAP may refer to:
* S.C.A.P., an early French manufacturer of cars and engines
* Security Content Automation Protocol
* '' The Shackled City Adventure Path'', a role-playing game
* SREBP cleavage activating protein
* Supervisory Capital Assessm ...
) and
HMG CoA reductase
HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, official symbol HMGCR) is the rate-limiting enzyme (NADH-dependent, ; NADPH-dependent, ) of the mevalonate pathway, the metabolic pathway that produces cholesterol and other ...
, 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
Sterol regulatory element-binding protein 2 (SREBP-2) also known as sterol regulatory element binding transcription factor 2 (SREBF2) is a protein that in humans is encoded by the SREBF2 gene.
Function
This gene encodes a ubiquitously expresse ...
.
References
Further reading
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External links
Uniprot description of INSIG1