| Modification Notes |
The transcription factors SREBPs (sterol regulatory element binding proteins) span the ER membrane, and in response to sterol depletion, the N-terminal domain of SREBPs are proteolytically activated, released from the membrane and then translocate to the nucleus where they induce the expression of genes regulating cholesterol metabolism (1). This proteolytic activation requires the sequential cleavage of SREBPs at Site-1, within the lumen of the ER, followed by cleavage at Site-2, within the first transmembrane domain (2). The cleavage at Site-1 separates the N-terminal and C-terminal domains of the protein and it requires the serine protease, S1P (Site-1 protease) (3,4). Site-2 is subsequently processed by a putative zinc metalloprotease S2P, which releases the activated N-terminal domain for nuclear translocation (2,5). This proteolytic pathway is tightly regulated by sterol levels and is under the control of SCAP (SREBP cleavage-activating protein) (6). SCAP, a sterol sensor, is latently bound to the C-terminal regulatory domains of the SREBPs, and it regulates cleavage of SREBPs at Site-1 (1,7). Sterol levels influence the activity of SCAP, as SCAP is activated only in sterol-depleted cells, and it is inhibited by sterol accumulation (8). |
