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-helix-loop-helix leucine zipper class of transcription factors. Unactivated SREBPs are attached to the nuclear envelope and 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 biosynthesis and for uptake and fatty acid 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 lipids (fats and oils) under widely varying circumstances (lipid homeostasis). For example, when cellular cholesterol 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 leads to the increased transcription of the target genes.
The ~120 kDa SREBP precursor protein is anchored in the membranes of the endoplasmic reticulum (ER) and nuclear envelope by virtue of two membrane-spanning helices in the middle of the protein. The precursor has a hairpin orientation in the membrane, so that both the amino-terminal transcription factor domain and the COOH-terminal regulatory domain face 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 proteases, called site-1 protease (S1P) and site-2 protease (S2P).