The gene encoding DRAP (BACE2), a glycosylated transmembrane protein of the aspartic protease family, maps to the Down critical region

We applied cDNA selection methods to a genomic clone (YAC 761B5) from chrom osome 21 located in the so-called 'Down critical region' in 21q22.3, Starti ng from human fetal heart and brain mRNAs we obtained and sequenced several cDWA clones. One of these clones (Down region aspartic protease (DRAP), na med also BACE2 according to the gene nomenclature) revealed a striking nucl eotide and amino acid sequence identity with several motifs present in memb ers of the aspartic protease family, In particular the amino acid sequences comprising the two catalytic sites found in all mammalian aspartic proteas es are perfectly conserved. Interestingly, the predicted protein shows a ty pical membrane spanning region; this is at variance with most other known a spartic proteases, which are soluble molecules. We present preliminary evid ence, on the basis of in vitro translation studies and cell transfection, t hat this gene encodes a glycosylated protein which localizes mainly intrace llularly but to some extent also to the plasma membrane. Furthermore DRAP/B ACE2 shares a high homology with a newly described beta-secretase enzyme (B ACE-1) which is a transmembrane aspartic protease, The implications of this finding for Down syndrome are discussed. (C) 2000 Federation of European B iochemical Societies.