title: Parkinson's disease-associated alpha-synuclein is a calmodulin substrate.
abstract: Alpha-synuclein is a neuronal protein thought to be central in the pathogenesis of Parkinson's disease (PD) because it comprises the fibrillar core of Lewy bodies, one of the histologically defining lesions of PD, and because mutations in alpha-synuclein cause autosomal dominant PD. Although its physiologic role is uncertain, alpha-synuclein is a synaptic protein that may contribute to plasticity. We produced synuclein with incorporated photoprobes to identify and purify novel synuclein-interacting proteins both to begin to clarify the physiology of synuclein and to identify factors that may regulate synuclein conformation. We detected several cross-links and purified and identified one as calmodulin (CaM). CaM binds to both wild type and PD-associated mutant alpha-synucleins in a calcium-dependent manner. We further demonstrate that CaM and alpha-synuclein interact in intact cells in a calcium-dependent manner and that activated CaM accelerates the formation of synuclein fibrils in vitro. We hypothesize that the known calcium control of synuclein function is mediated through CaM interaction and that CaM potentially alters synuclein conformation.
authors.affiliation: Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Martinez
authors.forename: Ines
authors.initials: I
authors.lastname: Moeller
authors.forename: Hediye
authors.initials: H
authors.lastname: Erdjument-Bromage
authors.forename: Paul
authors.initials: P
authors.lastname: Tempst
authors.forename: Brett
authors.initials: B
authors.lastname: Lauring
mesh_terms: D002147:Calmodulin / Q000378:metabolism*; D006801:Humans; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D013379:Substrate Specificity; D051843:Synucleins; D051844:alpha-Synuclein
chemical_list: D002147:Calmodulin; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein