SREBP cleavage-activating protein–Sterol regulatory element-binding protein 1 complex (SCAP–SREBP1)

The SREBP cleavage-activating protein–Sterol regulatory element-binding protein 1 (SCAP–SREBP1) complex is a central regulator of lipid biosynthesis in mammalian cells. SCAP functions as a sterol sensor and a molecular chaperone that binds to the C-terminal regulatory domain of SREBP1 within the endoplasmic reticulum (ER) membrane (UniProt: Q12770, P36956). When cellular sterol levels are low, the SCAP–SREBP1 complex is packaged into COPII-coated vesicles and translocated to the Golgi apparatus, where SREBP1 is proteolytically processed to release its transcriptionally active N-terminal fragment (Moon, J. Lipid Atheroscler., 2017). This active fragment then enters the nucleus to upregulate the expression of genes involved in fatty acid and triglyceride synthesis, such as fatty acid synthase (FASN) and stearoyl-CoA desaturase 1 (SCD1). Dysregulation of this pathway is a hallmark of metabolic diseases, including non-alcoholic fatty liver disease (NAFLD) and insulin resistance, as well as various cancers where de novo lipogenesis supports rapid tumor growth (Cheng et al., Cancer Commun., 2018). Small molecule inhibitors like fatostatin and betulin target this interface by binding to SCAP, thereby preventing the translocation of the complex and subsequent lipid production (Kamisuki et al., J. Biol. Chem., 2009; Tang et al., Cell Metab., 2011). Consequently, the SCAP–SREBP1 interface represents a promising therapeutic target for treating metabolic syndrome and lipid-dependent malignancies.

Other names

SCAP-SREBP1 interfaceSCAP-SREBP1 interactionSCAP-SREBP1 complex

Inhibition of the SCAP–SREBP1 complex translocation from the endoplasmic reticulum to the Golgi apparatus, preventing the proteolytic activation of SREBP1 and subsequent transcription of lipogenic genes (Kamisuki et al., J. Biol. Chem., 2009).