Genomic structure and chromosomal mapping of the human sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) gene.

Sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) is a central regulator of lipid synthesis and uptake in mammalian cells. The entire genomic structure of the human SCAP gene was cloned in a 110-kb region covered by overlapping genomic clones. The SCAP gene was localized to chromosome 3p21.3 by fluorescence in situ hybridization. The human SCAP gene is over 30 kb in length and contains 23 exons and 22 introns. The transcription initiation site within exon 1 is separate from the initiation codon coded in exon 2. Analysis of exon/intron structure revealed that the gene consists of a mosaic of exons encoding functional protein domains. Exon 1 encodes the 5' non-coding region. Exons 2, 3, 7, 8, 9, 10, 11, 13, and 15, respectively, encode each of the eight transmembrane regions. Of these, exons 7-11 encode the sterol-sensing domain. Exons 15-23 encode the hydrophilic carboxyl-terminal domains containing four copies of a motif called the Trp-Asp (WD) repeats that interact with and regulate SREBP and the site-1 protease. Sequence analysis of the 5'-flanking region showed that it comprised a high G/C-rich region and contained adipocyte determination and differentiation-dependent factor 1 (ADD1)/SREBP-1 binding sites in addition to Sp1 and AP2 sites. This suggests that SCAP gene expression is under the control of SREBP-1, a key regulator of the expression of genes essential for intracellular lipid metabolism. Our data establish the basis of investigation for molecular variants in this gene that may result in alterations in plasma lipoprotein levels and/or derangement of intracellular lipid metabolism.