Publication: The chaperonin CCT inhibits assembly of α-synuclein amyloid fibrils by a specific, conformation-dependent interaction.
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Identifiers
Date
2017-01-19
Authors
Sot, Begoña
Rubio-Muñoz, Alejandra
Leal-Quintero, Ahudrey
Martínez-Sabando, Javier
Marcilla, Miguel
Roodveldt, Cintia
Valpuesta, José M
Advisors
Journal Title
Journal ISSN
Volume Title
Publisher
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.
Description
MeSH Terms
Amyloid
Cell Line, Tumor
Chaperonin Containing TCP-1
Humans
Microscopy, Electron, Transmission
Mutagenesis, Site-Directed
Neurons
Protein Binding
Protein Multimerization
Protein Structure, Quaternary
Protein Subunits
alpha-Synuclein
Cell Line, Tumor
Chaperonin Containing TCP-1
Humans
Microscopy, Electron, Transmission
Mutagenesis, Site-Directed
Neurons
Protein Binding
Protein Multimerization
Protein Structure, Quaternary
Protein Subunits
alpha-Synuclein