title: Structural investigation of the C-terminal catalytic fragment of presenilin 1.
abstract: The gamma-secretase complex has a decisive role in the development of Alzheimer's disease, in that it cleaves a precursor to create the amyloid beta peptide whose aggregates form the senile plaques encountered in the brains of patients. Gamma-secretase is a member of the intramembrane-cleaving proteases which process their transmembrane substrates within the bilayer. Many of the mutations encountered in early onset familial Alzheimer's disease are linked to presenilin 1, the catalytic component of gamma-secretase, whose active form requires its endoproteolytic cleavage into N-terminal and C-terminal fragments. Although there is general agreement regarding the topology of the N-terminal fragment, studies of the C-terminal fragment have yielded ambiguous and contradictory results that may be difficult to reconcile in the absence of structural information. Here we present the first structure of the C-terminal fragment of human presenilin 1, as obtained from NMR studies in SDS micelles. The structure reveals a topology where the membrane is likely traversed three times in accordance with the more generally accepted nine transmembrane domain model of presenilin 1, but contains unique structural features adapted to accommodate the unusual intramembrane catalysis. These include a putative half-membrane-spanning helix N-terminally harboring the catalytic aspartate, a severely kinked helical structure toward the C terminus as well as a soluble helix in the assumed-to-be unstructured N-terminal loop.
authors.affiliation: Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance and Cluster of Excellence Macromolecular Complexes, Goethe University, 60438 Frankfurt/Main, Germany.
authors.forename: Solmaz
authors.initials: S
authors.lastname: Sobhanifar
authors.forename: Birgit
authors.initials: B
authors.lastname: Schneider
authors.forename: Frank
authors.initials: F
authors.lastname: Löhr
authors.forename: Daniel
authors.initials: D
authors.lastname: Gottstein
authors.forename: Teppei
authors.initials: T
authors.lastname: Ikeya
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Mlynarczyk
authors.forename: Wojciech
authors.initials: W
authors.lastname: Pulawski
authors.forename: Umesh
authors.initials: U
authors.lastname: Ghoshdastider
authors.forename: Michal
authors.initials: M
authors.lastname: Kolinski
authors.forename: Slawomir
authors.initials: S
authors.lastname: Filipek
authors.forename: Peter
authors.initials: P
authors.lastname: Güntert
authors.forename: Frank
authors.initials: F
authors.lastname: Bernhard
authors.forename: Volker
authors.initials: V
authors.lastname: Dötsch
mesh_terms: D000595:Amino Acid Sequence; D055162:Biocatalysis; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008051:Lipid Bilayers / Q000737:chemistry; D008823:Micelles; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D053764:Presenilin-1 / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D008051:Lipid Bilayers; D008823:Micelles; D053764:Presenilin-1
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