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Abstract

A significant proportion of early onset Alzheimer's disease (AD) is caused by mutations in human genes for amyloid precursor protein (APP), presenilins 1 and 2 (PSEN1,2). AD associated mutations in PSEN1,2 genes alter the gamma-secretase cleavage activity of APP resulting in increased production of amyloidogenic Abeta42. PSEN dependent intramembrane proteolysis was described as an important step required for cleavage of Notch receptors, Notch-dependent signal transduction, and processing of other proteins. It is still unclear whether presenilins are unusual intramembrane proteases or they are necessary cofactors of gamma-secretase cleavage of APP and Notch. Identification of other proteins similar to presenilins may resolve this dilemma. We describe here the identification of novel families of genes encoding polytopic transmembrane proteins of Eukaryotes (IMPASes) and Arachaea(membrases). These proteins have a predicted structure similar to presenilins. The amino acid similarity is significant in domains carrying invariant amino acid residues, which are critical in specific presenilin-regulated endoproteolysis. Many members of the IMPAS family have protease associated domains (PA) typical of proteases. We identified and cloned five human IMPAS genes. Expression analysis of the hIMP1 gene (located on chromosome 20) was performed in human cell tissues and transfected cell cultures. The data demonstrate that a conservative class of putative protease-related polytopic proteins related to presenilins exists in multicellular eukaryotes and microorganisms.

The Caenorhabditis elegans IMPAS gene, imp-2, is essential for development and is functionally distinct from related presenilins

“…At least five IMP genes in human and three diverged homologous genes similar to presenilins in C. elegans were identified. Comparison of the most conserved domains suggests links to a family of proteins in Archaea and to bacterial peptidases (12,15), indicating that C. elegans Ce-IMP-1, Ce-IMP-2, and Ce-IMP-3, like their human orthologs, may be polytopic proteases. The C. elegans Ce-IMP-1, Ce-IMP-2, and Ce-IMP-3 have divergent N termini but have substantial amino acid conservation in three hydrophobic regions predicted to be transmembrane (Tm) domains ( Fig.…”

“…The results demonstrate that PSs͞sel-12,hop-1 facilitate signaling by means of Notch͞lin-12,glp-1 receptors. Recently, genes encoding proteins homologous to PSs and termed IMPAS (or IMP͞PSH͞SPP,SPPL, hereafter referred to as IMPs) have been found (12)(13)(14), † †). The abundant ancient family of orthologous and paralogous IMP proteins is conserved from yeast to humans and share structural similarities with Archaea proteins and prokaryotic type 4 prepilin peptidases (TFPP) (15).…”

Moonlighting activity of presenilin in plants is independent of γ-secretase and evolutionarily conserved

“…In contrast, PS and related proteins have been identified in both metazoans and plants (44)(45)(46)(47)(48). Similar to the genomes of Arabidopsis (Dicot) and Oryza sativa (monocot), whose complete genome sequences are available, an early land plant, the moss Physcomitrella patens, also harbors all four components of ␥-secretase.…”

A Signal Peptide Peptidase (SPP) Reporter Activity Assay Based on the Cleavage of Type II Membrane Protein Substrates Provides Further Evidence for an Inverted Orientation of the SPP Active Site Relative to Presenilin

“…Signal peptide peptidase (SPP) 1 is a multipass membrane protein (1)(2)(3)(4)(5)(6)(7)(8) that has been shown to carry out the intramembrane cleavage of type II membrane protein signal peptides after the initial cleavage of these by signal peptidase (Fig. 1a) (1).…”

“…SPP is a member of a family of homologous multipass membrane proteins, which includes presenilin 1 (PS1) and 2 (PS2) (1,2,6). Intramembrane cleavage by members of this family is thought to be catalyzed by two aspartates present in adjacent transmembrane domains (Fig.…”