SREBP cleavage-activating protein

SREBP cleavage-activating protein (SCAP) is a crucial component in the regulation of lipid homeostasis. It is involved in the SREBP (Sterol Regulatory Element-Binding Proteins) pathway, which controls the synthesis of cholesterol and fatty acids in the body.

Function

SCAP is an integral membrane protein located in the endoplasmic reticulum (ER). It functions as a sterol sensor and is responsible for the transport of SREBPs from the ER to the Golgi apparatus. In the Golgi, SREBPs undergo two sequential proteolytic cleavages, which release the active form of SREBPs that can enter the nucleus and activate the transcription of genes involved in lipid biosynthesis.

Mechanism

Under conditions of low cellular cholesterol, SCAP escorts SREBPs to the Golgi apparatus. This process is facilitated by the interaction of SCAP with COPII vesicles, which mediate the transport of proteins from the ER to the Golgi. Once in the Golgi, SREBPs are cleaved by site-1 protease (S1P) and site-2 protease (S2P), releasing the N-terminal domain of SREBPs. This domain then translocates to the nucleus, where it binds to sterol regulatory elements (SREs) in the promoter regions of target genes, enhancing their transcription.

Regulation

The activity of SCAP is tightly regulated by the sterol content of the cell. When cholesterol levels are high, SCAP undergoes a conformational change that prevents its interaction with COPII vesicles, thereby retaining SREBPs in the ER and reducing the transcription of lipid biosynthetic genes. This feedback mechanism ensures that cholesterol synthesis is decreased when cellular cholesterol is sufficient.

Clinical Significance

Mutations in the SCAP gene can lead to dysregulation of lipid metabolism, contributing to conditions such as hypercholesterolemia and atherosclerosis. Understanding the role of SCAP in lipid homeostasis is crucial for developing therapeutic strategies for these metabolic disorders.

See Also

• Cholesterol metabolism
• Lipid biosynthesis
• Endoplasmic reticulum
• Golgi apparatus

External Links

• [SCAP at UniProt](https://www.uniprot.org/uniprot/Q12770)
• [SCAP Gene - GeneCards](https://www.genecards.org/cgi-bin/carddisp.pl?gene=SCAP)