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PrP charge structure encodes interdomain interactions.

  • Martínez J Instituto Química-Física "Rocasolano", Consejo Superior de Investigaciones Científicas, Madrid 28006, Spain.
  • Sánchez R Instituto Química-Física "Rocasolano", Consejo Superior de Investigaciones Científicas, Madrid 28006, Spain.
  • Castellanos M Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Madrid, Spain; IMDEA-Nanociencia, Madrid 28049, Spain.
  • Makarava N Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
  • Aguzzi A Institute of Neuropathology, University Hospital of Zürich, Zürich 8091, Switzerland.
  • Baskakov IV Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
  • Gasset M Instituto Química-Física "Rocasolano", Consejo Superior de Investigaciones Científicas, Madrid 28006, Spain.
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  • 2015-09-02
Published in:
  • Scientific reports. - 2015
Circular Dichroism
Dynamic Light Scattering
Humans
Hydrogen-Ion Concentration
Mutagenesis, Site-Directed
Prions
Protein Folding
Protein Structure, Secondary
Protein Structure, Tertiary
Static Electricity
English Almost all proteins contain charged residues, and their chain distribution is tailored to fulfill essential ionic interactions for folding, binding and catalysis. Among proteins, the hinged two-domain chain of the cellular prion protein (PrP(C)) exhibits a peculiar charge structure with unclear consequences in its structural malleability. To decipher the charge design role, we generated charge-reverted mutants for each domain and analyzed their effect on conformational and metabolic features. We found that charges contain the information for interdomain interactions. Use of dynamic light scattering and thermal denaturation experiments delineates the compaction of the α-fold by an electrostatic compensation between the polybasic 23-30 region and the α3 electronegative surface. This interaction increases stability and disfavors fibrillation. Independently of this structural effect, the N-terminal electropositive clusters regulate the α-cleavage efficiency. In the fibrillar state, use of circular dichroism, atomic-force and fluorescence microscopies reveal that the N-terminal positive clusters and the α3 electronegative surface dictate the secondary structure, the assembly hierarchy and the growth length of the fibril state. These findings show that the PrP charge structure functions as a code set up to ensure function and reduce pathogenic routes.
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  • English
Open access status
gold
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Persistent URL
https://sonar.ch/global/documents/66367
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