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Novel quaternary structures of the human prion protein globular domain

DOI: 10.1016/j.biochi.2021.09.005 DOI Help

Authors: Leandro Oliveira Bortot (University of São Paulo) , Victor Lopes Rangel (University of São Paulo) , Francesca A. Pavlovici (Broad Institute of MIT and Harvard) , Kamel El Omari (Diamond Light Source) , Armin Wagner (Diamond Light Source) , Jose Brandao-Neto (Diamond Light Source) , Romain Talon (Diamond Light Source) , Frank Von Delft (Diamond Light Source; Structural Genomics Consortium, University of Oxford; University of Johannesburg) , Andrew G. Reidenbach (Broad Institute of MIT and Harvard) , Sonia M. Vallabh (Broad Institute of MIT and Harvard) , Eric Vallabh Minikel (Broad Institute of MIT and Harvard) , Stuart Schreiber (Broad Institute of MIT and Harvard; Harvard University) , Maria Cristina Nonato (University of São Paulo)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Biochimie , VOL 191 , PAGES 118 - 125

State: Published (Approved)
Published: December 2021
Diamond Proposal Number(s): 18954

Abstract: Prion disease is caused by the misfolding of the cellular prion protein, PrPC, into a self-templating conformer, PrPSc. Nuclear magnetic resonance (NMR) and X-ray crystallography revealed the 3D structure of the globular domain of PrPC and the possibility of its dimerization via an interchain disulfide bridge that forms due to domain swap or by non-covalent association of two monomers. On the contrary, PrPSc is composed by a complex and heterogeneous ensemble of poorly defined conformations and quaternary arrangements that are related to different patterns of neurotoxicity. Targeting PrPC with molecules that stabilize the native conformation of its globular domain emerged as a promising approach to develop anti-prion therapies. One of the advantages of this approach is employing structure-based drug discovery methods to PrPC. Thus, it is essential to expand our structural knowledge about PrPC as much as possible to aid such drug discovery efforts. In this work, we report a crystallographic structure of the globular domain of human PrPC that shows a novel dimeric form and a novel oligomeric arrangement. We use molecular dynamics simulations to explore its structural dynamics and stability and discuss potential implications of these new quaternary structures to the conversion process.

Journal Keywords: Prion; X-ray crystallography; Anomalous scattering; Amyloid

Subject Areas: Biology and Bio-materials

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I23-Long wavelength MX

Added On: 19/09/2021 10:38

Discipline Tags:

Neurodegenerative Diseases Non-Communicable Diseases Health & Wellbeing Neurology Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX) Long Wavelength Crystallography