We identified novel family of related proteins with multiple transmembrane domains encoded by orthologous and paralogous genes in Eukaryotes .We searched for ancient types of presenilins (PSs) and identified homologous genes in Protista. The presenilin like sequence in Protista has the shortest loop among all known orthologous and paralogous presenilin sequences. The search for proteins similar to presenilin prototype revealed a large family of proteins with identical formula of amino-acid sequences in multiple homologs from yeast to human. These proteins have predicted structures similar to presenilins. The most significant similarities are observed in domains with aspartate residues which are critical for putative intra-membrane proteolysis associated activity of presenilins. Therefore, the abundant class of these novel proteins was termed IMPAS (IMP). We found similar family of the proteins in Archaea. We have cloned and analyzed five human IMPAS genes: hImp1(chr 20), hImp2 (chr 12), hImp3 (chr 15), hImp 4 (chr 19), hImp5 (chr 17). The regions of locations include loci implicated for neuro-psychiatric diseases. In addition we identified two pseudo-genes of human IMPAS family. The analysis of expression demonstrated widespread expression of four IMP genes in human tissues, including brain. In addition, we found that several members of IMP have protease specific PA domains. IMPs with and without PA domains are modified in mammalian cells. Thus, the Alzheimer’s disease PS and IMPs are related families of abundant class of unusual membrane proteins which are proteases per ser or are critical-cofactors for intra-membrane proteolysis.predict that 1) members of IMP family have function unrelated to signal peptide peptidase (SPP) activity described recently by in vitro assay; 2) the IMPs proteolytic function may be inhibited by pharmacological approaches proposed for modulation of AD-pathway. The data supporting these predictions will be presented. The elucidation of functions of different members of the IMPAS proteins is of significant interest for understanding of conserved mechanisms of membrane associated proteolysis and signaling in normal cellular functions and human pathologies
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