Sterol regulatory element binding protein
Encyclopedia
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s that bind to the sterol
Sterol
Sterols, also known as steroid alcohols, are a subgroup of the steroids and an important class of organic molecules. They occur naturally in plants, animals, and fungi, with the most familiar type of animal sterol being cholesterol...
regulatory element DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
sequence TCACNCCAC. Mammalian SREBPs are encoded by the genes SREBF1
SREBF1
Sterol regulatory element-binding transcription factor 1 also known as sterol regulatory element-binding protein 1 is a protein that in humans is encoded by the SREBF1 gene....
and SREBF2
SREBF2
Sterol regulatory element-binding protein 2 also known as sterol regulatory element binding transcription factor 2 is a protein that in humans is encoded by the SREBF2 gene.- Function :...
. SREBPs belong to the basic-helix-loop-helix
Basic-helix-loop-helix
A basic helix-loop-helix is a protein structural motif that characterizes a family of transcription factors.- Structure :The motif is characterized by two α-helices connected by a loop. In general, transcription factors including this domain are dimeric, each with one helix containing basic amino...
leucine zipper
Leucine zipper
A leucine zipper, aka leucine scissors, is a common three-dimensional structural motif in proteins. These motifs are usually found as part of a DNA-binding domain in various transcription factors, and are therefore involved in regulating gene expression...
class of transcription factors. Unactivated SREBPs are attached to the nuclear envelope
Nuclear envelope
A nuclear envelope is a double lipid bilayer that encloses the genetic material in eukaryotic cells. The nuclear envelope also serves as the physical barrier, separating the contents of the nucleus from the cytosol...
and endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
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. SREBP-2 regulates the genes of cholesterol metabolism.
Function
SREB proteins are indirectly required for cholesterolCholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
biosynthesis and for uptake and fatty acid
Fatty acid
In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...
biosynthesis. These proteins work with asymmetric sterol regulatory element (StRE). SREBPs have a structure similar to E-box
E-box
An E-box is a DNA sequence which usually lies upstream of a gene in a promoter region. It is a transcription factor binding site where the specific sequence of DNA, CANNTG, is recognized by proteins that can bind to it to help initiate its transcription. Once transcription factors bind to...
-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 lipidLipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
s (fats and oils) under widely varying circumstances (lipid homeostasis
Homeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
). For example, when cellular cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
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 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
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
leads to the increased transcription of the target genes
Gênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...
.
The ~120 kDa SREBP precursor protein is anchored in the membranes of the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
(ER) and nuclear envelope by virtue of two membrane-spanning helices in the middle of the protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
. The precursor has a hairpin orientation in the membrane, so that both the amino-terminal transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
domain and the COOH-terminal regulatory domain face the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
. 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
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
s, called site-1 protease (S1P
Membrane-bound transcription factor peptidase, site 1
Membrane-bound transcription factor peptidase, site 1 also known as Site-1 Protease is an enzyme encoded by the gene which cleaves the endoplasmic reticulum loop of sterol regulatory element binding protein transcription factors....
) and site-2 protease (S2P
Membrane-bound transcription factor peptidase, site 2
Membrane-bound transcription factor peptidase, site 2 also known as Site-2 Protease is an enzyme encoded by the gene which liberates the N-terminal fragment of sterol regulatory element binding protein transcription factors from membranes . S2P cleaves the transmembrane domain of SREPB, making...
).
In addition to S1P and S2P, the regulated release of transcriptionally active SREBP requires the cholesterol-sensing protein SREBP cleavage activating protein (Scap
SREBP cleavage activating protein
Sterol regulatory element-binding protein cleavage-activating protein, also known as SREBP cleavage-activating protein or SCAP is a protein that in humans is encoded by the SCAP gene....
), 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
LDL receptor
The Low-Density Lipoprotein Receptor is a mosaic protein of ~840 amino acids that mediates the endocytosis of cholesterol-rich LDL. It is a cell-surface receptor that recognizes the apoprotein B100 which is embedded in the phospholipid outer layer of LDL particles...
gene)
Regulation
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 LXRLiver X receptor
The liver X receptor is a member of the nuclear receptor family of transcription factors and is closely related to nuclear receptors such as the PPARs, FXR and RXR. Liver X receptors are important regulators of cholesterol, fatty acid, and glucose homeostasis...
(LXRE) response elements are involved in SREBP1c transcription regulation mediated by insulin and cholesterol derivatives. Peroxisome proliferation-activated receptor alpha (PPARα
Peroxisome proliferator-activated receptor alpha
Peroxisome proliferator-activated receptor alpha , also known as NR1C1 , is a nuclear receptor protein that in humans is encoded by the PPARA gene.- Function :...
) agonists enhance the activity of the SREBP1c 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 SREBP1c gene via the mTORC1/S6K1
P70-S6 Kinase 1
Ribosomal protein S6 kinase beta-1 is an enzyme that in humans is encoded by the RPS6KB1 gene.-Interactions:P70-S6 Kinase 1 has been shown to interact with CSNK2B, EIF3B, COASY, KIAA1303, POLDIP3, Mammalian target of rapamycin, PPP2R2A, RBX1 and Ubiquitin C.-References:...
pathway. The phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
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 SREBP1c 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 SREBP1c in the absence of Akt signaling
Akt/PKB signaling pathway
The Akt/PKB signaling pathway is a pathway in cell signaling.Proteins involved include AKT and phosphoinositide 3-kinase .It can be associated with cancer....
, revealing the existence of an additional downstream pathway also required for this induction which is proposed to involve mTORC1-independent Akt-mediated suppression of Insig2a
INSIG2
Insulin induced gene 2, also known as INSIG2, is a protein which in humans is encoded by the INSIG2 gene.- Regulation :Insulin activates the human INSIG2 promoter in a process mediated by phosphorylated SAP1a....
, a liver-specific transcript encoding the SREBP1c inhibitor INSIG2.
FGF21
FGF21
Fibroblast growth factor 21 is a protein that in humans is encoded by the FGF21 gene. The protein encoded by this gene is a member of the fibroblast growth factor family...
has been shown to repress the transcription of sterol regulatory element binding protein 1c (SREBP1c). Overexpression of FGF21 ameliorated the up-regulation of SREBP1c 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 SREBP1c, and decrease the protein amount of mature SREBP1c. Unexpectedly, overexpression of SREBP1c in HepG2 cells could also inhibit the endogenous FGF21 transcription by reducing FGF21 promoter activity.
SREBP1c has also been shown to upregulate in a tissue specific manner the expression of PGC1alpha
PPARGC1A
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha is a protein that in humans is encoded by the PPARGC1A gene....
expression in brown adipose tissue.
Nur77
Nerve Growth factor IB
The nerve Growth factor IB also known as Nur77 or NR4A1 is a protein that in humans is encoded by the NR4A1 gene....
is suggested to inhibit LXR and downstream SREBP1c expression modulating hepatic lipid metabolism.
External links
- The Brown and Goldstein Lab.
- Cholesterol Synthesis - has some good regulatory details
- Protein Data Base (PDB), Sterol Regulatory Element Binding 1A structure.