title: The chaperonin CCT inhibits assembly of α-synuclein amyloid fibrils by a specific, conformation-dependent interaction.
abstract: The eukaryotic chaperonin CCT (chaperonin containing TCP-1) uses cavities built into its double-ring structure to encapsulate and to assist folding of a large subset of proteins. CCT can inhibit amyloid fibre assembly and toxicity of the polyQ extended mutant of huntingtin, the protein responsible for Huntington's disease. This raises the possibility that CCT modulates other amyloidopathies, a still-unaddressed question. We show here that CCT inhibits amyloid fibre assembly of α-synuclein A53T, one of the mutants responsible for Parkinson's disease. We evaluated fibrillation blockade in α-synuclein A53T deletion mutants and CCT interactions of full-length A53T in distinct oligomeric states to define an inhibition mechanism specific for α-synuclein. CCT interferes with fibre assembly by interaction of its CCTζ and CCTγ subunits with the A53T central hydrophobic region (NAC). This interaction is specific to NAC conformation, as it is produced once soluble α-synuclein A53T oligomers form and blocks the reaction before fibres begin to grow. Finally, we show that this association inhibits α-synuclein A53T oligomer toxicity in neuroblastoma cells. In summary, our results and those for huntingtin suggest that CCT is a general modulator of amyloidogenesis via a specific mechanism.
authors.affiliation: Departamento de Estructura de Macromoléculas, Centro Nacional de Biotecnología (CNB-CSIC), Campus de la Universidad Autónoma de Madrid, 28049 Madrid, Spain.|Fundación IMDEA-Nanociencia, Campus de la Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: Sot
authors.affiliation: Departamento de Estructura de Macromoléculas, Centro Nacional de Biotecnología (CNB-CSIC), Campus de la Universidad Autónoma de Madrid, 28049 Madrid, Spain.|Fundación IMDEA-Nanociencia, Campus de la Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Rubio-Muñoz
authors.affiliation: Departamento de Estructura de Macromoléculas, Centro Nacional de Biotecnología (CNB-CSIC), Campus de la Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: Ahudrey
authors.initials: A
authors.lastname: Leal-Quintero
authors.affiliation: Departamento de Estructura de Macromoléculas, Centro Nacional de Biotecnología (CNB-CSIC), Campus de la Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Martínez-Sabando
authors.affiliation: Unidad de Proteómica, Centro Nacional de Biotecnología (CNB-CSIC), Campus de la Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Marcilla
authors.affiliation: Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER)-Spanish National Research Council (CSIC), Universidad Pablo de Olavide, University of Seville, Seville, Spain.
authors.forename: Cintia
authors.initials: C
authors.lastname: Roodveldt
authors.affiliation: Departamento de Estructura de Macromoléculas, Centro Nacional de Biotecnología (CNB-CSIC), Campus de la Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Valpuesta
mesh_terms: D000682:Amyloid / Q000378:metabolism* / Q000633:toxicity; D045744:Cell Line, Tumor; D056404:Chaperonin Containing TCP-1 / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D046529:Microscopy, Electron, Transmission; D016297:Mutagenesis, Site-Directed; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D000682:Amyloid; D021122:Protein Subunits; D051844:alpha-Synuclein; D056404:Chaperonin Containing TCP-1