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Sterol regulatory element-binding proteins (SREBPs) are
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
s that bind to the
sterol Sterol is an organic compound with formula , whose molecule is derived from that of gonane by replacement of a hydrogen atom in position 3 by a hydroxyl group. It is therefore an alcohol of gonane. More generally, any compounds that contain the g ...
regulatory element DNA sequence TCACNCCAC. Mammalian SREBPs are encoded by the genes '' SREBF1'' and '' SREBF2''. SREBPs belong to the basic-helix-loop-helix leucine zipper class of transcription factors. Unactivated SREBPs are attached to the nuclear envelope and
endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...
membranes. In cells with low levels of sterols, SREBPs are cleaved to a water-soluble N-terminal domain that is translocated to the nucleus. These activated SREBPs then bind to specific sterol regulatory element DNA sequences, thus upregulating the synthesis of enzymes involved in sterol biosynthesis. Sterols in turn inhibit the cleavage of SREBPs and therefore synthesis of additional sterols is reduced through a negative feed back loop.


Isoforms

Mammalian genomes have two separate SREBP genes ( and ): * SREBP-1 expression produces two different isoforms, SREBP-1a and -1c. These isoforms differ in their first exons owing to the use of different transcriptional start sites for the SREBP-1 gene. SREBP-1c was also identified in rats as ADD-1. SREBP-1c is responsible for regulating the genes required for ''de novo'' lipogenesis. * SREBP-2 regulates the genes of cholesterol metabolism.


Function

SREB proteins are indirectly required for
cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell membr ...
biosynthesis and for uptake and
fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...
biosynthesis. These proteins work with asymmetric sterol regulatory element (StRE). SREBPs have a structure similar to E-box-binding helix-loop-helix (HLH) proteins. However, in contrast to E-box-binding HLH proteins, an arginine residue is replaced with tyrosine making them capable of recognizing StREs and thereby regulating membrane biosynthesis.


Mechanism of action

Animal cells maintain proper levels of intracellular
lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids incl ...
s (fats and oils) under widely varying circumstances (lipid
homeostasis In biology, homeostasis (British English, British also homoeostasis) Help:IPA/English, (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physics, physical, and chemistry, chemical conditions maintained by organism, living systems. Thi ...
). For example, when cellular
cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell membr ...
levels fall below the level needed, the cell makes more of the enzymes necessary to make cholesterol. A principal step in this response is to make more of the
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the ...
transcripts that direct the synthesis of these enzymes. Conversely, when there is enough cholesterol around, the cell stops making those mRNAs and the level of the enzymes falls. As a result, the cell quits making cholesterol once it has enough. A notable feature of this regulatory feedback machinery was first observed for the SREBP pathway - regulated intramembrane proteolysis (RIP). Subsequently, RIP was found to be used in almost all organisms from bacteria to human beings and regulates a wide range of processes ranging from development to neurodegeneration. A feature of the SREBP pathway is the proteolytic release of a membrane-bound transcription factor, SREBP. Proteolytic cleavage frees it to move through the cytoplasm to the nucleus. Once in the nucleus, SREBP can bind to specific DNA sequences (the sterol regulatory elements or SREs) that are found in the control regions of the genes that encode enzymes needed to make lipids. This binding to DNA leads to the increased transcription of the target
genes In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
. The ~120 kDa SREBP precursor protein is anchored in the membranes of the
endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...
(ER) and nuclear envelope by virtue of two membrane-spanning helices in the middle of the
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...
. The precursor has a hairpin orientation in the membrane, so that both the amino-terminal
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
domain and the COOH-terminal regulatory domain face the
cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
. The two membrane-spanning helices are separated by a loop of about 30 amino acids that lies in the lumen of the ER. Two separate, site-specific proteolytic cleavages are necessary for release of the transcriptionally active amino-terminal domain. These cleavages are carried out by two distinct
protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the form ...
s, called site-1 protease (
S1P Sphingosine-1-phosphate (S1P) is a signaling sphingolipid, also known as lysosphingolipid. It is also referred to as a bioactive lipid mediator. Sphingolipids at large form a class of lipids characterized by a particular aliphatic aminoalcohol, ...
) and site-2 protease ( S2P). In addition to S1P and S2P, the regulated release of transcriptionally active SREBP requires the cholesterol-sensing protein SREBP cleavage-activating protein ( SCAP), which forms a complex with SREBP owing to interaction between their respective carboxy-terminal domains. SCAP, in turn, can bind reversibly with another ER-resident membrane protein, INSIG. In the presence of sterols, which bind to INSIG and SCAP, INSIG and SCAP also bind one another. INSIG always stays in the ER membrane and thus the SREBP-SCAP complex remains in the ER when SCAP is bound to INSIG. When sterol levels are low, INSIG and SCAP no longer bind. Then, SCAP undergoes a conformational change that exposes a portion of the protein ('MELADL') that signals it to be included as cargo in the COPII vesicles that move from the ER to the Golgi apparatus. In these vesicles, SCAP, dragging SREBP along with it, is transported to the Golgi. The regulation of SREBP cleavage employs a notable feature of eukaryotic cells, subcellular compartmentalization defined by intracellular membranes, to ensure that cleavage occurs only when needed. Once in the Golgi apparatus, the SREBP-SCAP complex encounters active S1P. S1P cleaves SREBP at site-1, cutting it into two halves. Because each half still has a membrane-spanning helix, each remains bound in the membrane. The newly generated amino-terminal half of SREBP (which is the ‘business end' of the molecule) then goes on to be cleaved at site-2 that lies within its membrane-spanning helix. This is the work of S2P, an unusual metalloprotease. This releases the cytoplasmic portion of SREBP, which then travels to the nucleus where it activates transcription of target genes (e.g. LDL receptor gene)


Regulation

Absence of sterols activates SREBP, thereby increasing cholesterol synthesis. Insulin, cholesterol derivatives, T3 and other endogenous molecules have been demonstrated to regulate the SREBP1c expression, particularly in rodents. Serial deletion and mutation assays reveal that both SREBP (SRE) and LXR (LXRE) response elements are involved in SREBP-1c transcription regulation mediated by insulin and cholesterol derivatives. Peroxisome proliferation-activated receptor alpha ( PPARα) agonists enhance the activity of the SREBP-1c promoter via a DR1 element at -453 in the human promoter. PPARα agonists act in cooperation with LXR or insulin to induce lipogenesis. A medium rich in branched-chain amino acids stimulates expression of the SREBP-1c gene via the mTORC1/ S6K1 pathway. The
phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, ...
of S6K1 was increased in the liver of obese db/db mice. Furthermore, depletion of hepatic S6K1 in db/db mice with the use of an adenovirus vector encoding S6K1 shRNA resulted in down-regulation of SREBP-1c gene expression in the liver as well as a reduced hepatic triglyceride content and serum triglyceride concentration. mTORC1 activation is not sufficient to stimulate hepatic SREBP-1c in the absence of Akt signaling, revealing the existence of an additional downstream pathway also required for this induction which is proposed to involve mTORC1-independent Akt-mediated suppression of INSIG-2a, a liver-specific transcript encoding the SREBP-1c inhibitor INSIG2. FGF21 has been shown to repress the transcription of sterol regulatory element binding protein 1c (SREBP-1c). Overexpression of FGF21 ameliorated the up-regulation of SREBP-1c and fatty acid synthase (FAS) in HepG2 cells elicited by FFAs treatment. Moreover, FGF21 could inhibit the transcriptional levels of the key genes involved in processing and nuclear translocation of SREBP-1c, and decrease the protein amount of mature SREBP-1c. Unexpectedly, overexpression of SREBP-1c in HepG2 cells could also inhibit the endogenous FGF21 transcription by reducing FGF21 promoter activity. SREBP-1c has also been shown to upregulate in a tissue specific manner the expression of PGC1alpha expression in brown adipose tissue. Nur77 is suggested to inhibit LXR and downstream SREBP-1c expression modulating hepatic lipid metabolism.


History

The SREBPs were elucidated in the laboratory of Nobel laureates Michael Brown and Joseph Goldstein at the University of Texas Southwestern Medical Center in Dallas. Their first publication on this subject appeared in October 1993.


References


External links

*
The Brown and Goldstein Lab


- has some good regulatory details
Protein Data Base (PDB)
Sterol Regulatory Element Binding 1A structure. {{Transcription factors, g1 Transcription factors