title: Linear patterns of Alzheimer's disease mutations along alpha-helices of presenilins as a tool for PS-1 model construction.
abstract: We performed an analysis of mutation patterns in all 10 hydrophobic regions (HRs) of presenilin-1 (PS-1) and PS-2 using a recent database of Alzheimer's disease (AD) mutations. The linear patterns were confirmed and extended to areas spanning as many as three faces of a given HR. The complementary areas of residues free of AD mutations were identified based on the location of non-pathogenic polymorphisms and PS-1 versus PS-2 amino acid discordances. Taking into account the location of areas of AD mutations and mutation-free areas/regions, we proposed a preliminary model of PS-1 structure using a general stick-out-mutation rule. To build a molecular structure of PS-1 and preserve features of the preliminary model, we used bacteriorhodopsin template in homology/comparative modelling. Two molecular models were built differing in the location of C-terminal fragment helices. The models properly distinguish residues belonging to AD-affected sites and non-pathogenic areas, and may be used for classification purposes. They also comply with experimental results, such as differences in accessibility of the catalytic residues in uncleaved PS-1, and binding of PEN-2 by the PS-1 NF motif.
authors.affiliation: International Institute of Molecular and Cell Biology, Warsaw, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Jozwiak
authors.forename: Cezary
authors.initials: C
authors.lastname: Zekanowski
authors.forename: Slawomir
authors.initials: S
authors.lastname: Filipek
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D019943:Amino Acid Substitution / Q000502:physiology; D000818:Animals; D002474:Cell-Free System; D005820:Genetic Testing; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics*; D008958:Models, Molecular; D009154:Mutation / Q000502:physiology*; D053764:Presenilin-1; D017433:Protein Structure, Secondary / Q000502:physiology
chemical_list: D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1