2.A.6.6.16
Sterol regulatory element-binding protein cleavage-activating protein, SCAP (SLC64 Family), an SSD domain-containing protein of 731 aas and 7 TMSs in a 1 + 5 + 1 TMS arrangement. The cholesterol-sensing protein Scap induces cholesterol synthesis by transporting membrane-bound transcription factors called sterol regulatory element-binding proteins (SREBPs) from the theendoplasmic reticulum (ER) to the Golgi apparatus for proteolytic activation. Transport requires interaction between Scap's two ER luminal loops (L1 and L7), which flank an intramembrane sterol-sensing domain (SSD). Cholesterol inhibits Scap transport by binding to L1, which triggers Scap's binding to Insig, an ER retention protein. Kober et al. 2021 used cryo-EM to elucidate two structures of full-length chicken Scap: (1) a wild-type free of Insigs and (2) mutant Scap bound to chicken Insig without cholesterol.  L1 and L7 intertwine tightly to form a globular domain that acts as a luminal platform connecting the SSD to the rest of Scap. In the presence of Insig, this platform undergoes a large rotation accompanied by rearrangement of Scap's transmembrane helices. This conformational change may halt Scap transport of SREBPs and thereby inhibit cholesterol synthesis (Kober et al. 2021).