title: Mutation E46K increases phospholipid binding and assembly into filaments of human alpha-synuclein.
abstract: Missense mutations (A30P and A53T) in alpha-synuclein and the overproduction of the wild-type protein cause familial forms of Parkinson's disease and dementia with Lewy bodies. Alpha-synuclein is the major component of the filamentous Lewy bodies and Lewy neurites that define these diseases at a neuropathological level. Recently, a third missense mutation (E46K) in alpha-synuclein was described in an inherited form of dementia with Lewy bodies. Here, we have investigated the functional effects of this novel mutation on phospholipid binding and filament assembly of alpha-synuclein. When compared to the wild-type protein, the E46K mutation caused a significantly increased ability of alpha-synuclein to bind to negatively charged liposomes, unlike the previously described mutations. The E46K mutation increased the rate of filament assembly to the same extent as the A53T mutation. Filaments formed from E46K alpha-synuclein often had a twisted morphology with a cross-over spacing of 43 nm. The observed effects on lipid binding and filament assembly may explain the pathogenic nature of the E46K mutation in alpha-synuclein.
authors.affiliation: MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK.
authors.forename: Woong
authors.initials: W
authors.lastname: Choi
authors.forename: Shahin
authors.initials: S
authors.lastname: Zibaee
authors.forename: Ross
authors.initials: R
authors.lastname: Jakes
authors.forename: Louise C
authors.initials: LC
authors.lastname: Serpell
authors.forename: Bazbek
authors.initials: B
authors.lastname: Davletov
authors.forename: R Anthony
authors.initials: RA
authors.lastname: Crowther
authors.forename: Michel
authors.initials: M
authors.lastname: Goedert
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D006801:Humans; D007700:Kinetics; D007739:L Cells; D020961:Lewy Body Disease / Q000235:genetics; D008081:Liposomes; D051379:Mice; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism / Q000648:ultrastructure; D010300:Parkinson Disease / Q000235:genetics; D010743:Phospholipids / Q000378:metabolism; D051843:Synucleins; D051844:alpha-Synuclein
chemical_list: D008081:Liposomes; D009419:Nerve Tissue Proteins; D010743:Phospholipids; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein