Sterol regulatory element-binding protein

In cells with low levels of sterols, SREBPs are cleaved to a water-soluble N-terminal domain that is translocated to the nucleus.

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.

A notable feature of this regulatory feedback machinery was first observed for the SREBP pathway - regulated intramembrane proteolysis (RIP).

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.

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.

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.

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.

[13] 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.

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.

[17] 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.

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SREBP activation by proteolytic cleavage. SREBP precursors are retained in the ER Tooltip endoplasmic reticulum membranes through a tight association with SCAP Tooltip SREBP cleavage-activating protein and a protein of the INSIG Tooltip insulin-induced gene protein family. Under the appropriate conditions, SCAP dissociates from INSIG and escorts the SREBP precursors from the ER to the Golgi apparatus . Once there, two proteases, S1P Tooltip site-1 protease and S2P Tooltip site-2 protease , sequentially cleave the precursor protein, releasing the mature form of SREBPs into the cytoplasm. The mature form then migrates to the nucleus, where it activates the promoter of genes involved in cholesterol uptake or in cholesterol synthesis . SREBP processing can be controlled by the cellular sterol content.