title: Structure nor stability of the transmembrane spanning 6/7 domain of presenilin I correlates with pathogenicity.
abstract: Since its cloning in 1995, missense point mutations in presenilin I (PS-I) have been shown to be responsible for greater than 70% of the cases of early onset familial Alzheimer's disease (EOFAD), which can affect individuals as early as age 18. PS-I is known to be a component of gamma-secretase, the enzyme responsible for cleavage of the amyloid precursor protein (APP) into 42 amino acid peptides that aggregate to form the plaques surrounding neurons of Alzheimer's patients. It has recently been hypothesized that wild-type (wt) PS-I contains an autoinhibitory module that prevents gamma-secretase cleavage of the APP, while pathogenic PS-I point mutants lack a structure necessary for this inhibition. In this work, spectroscopic data is presented that does not correlate structure or stability of the proposed PS-I autoinhibitory module with pathogenicity.
authors.affiliation: Department of Chemistry, Western Washington University, Bellingham, WA 98225-9150, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Jeppesen
authors.forename: Laura
authors.initials: L
authors.lastname: Costello
authors.forename: Adam
authors.initials: A
authors.lastname: Fung
authors.forename: Erin
authors.initials: E
authors.lastname: Stanley
authors.forename: Jessica
authors.initials: J
authors.lastname: McDonald
authors.forename: Abbie
authors.initials: A
authors.lastname: Lambert
authors.forename: Bennett
authors.initials: B
authors.lastname: Johnson
authors.forename: Lisa
authors.initials: L
authors.lastname: Gentile
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D002462:Cell Membrane / Q000737:chemistry; D006358:Hot Temperature; D006801:Humans; D017354:Point Mutation; D053764:Presenilin-1 / Q000737:chemistry* / Q000235:genetics; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013050:Spectrometry, Fluorescence
chemical_list: D053764:Presenilin-1