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Novel quaternary structures of the human prion protein globular domain
DOI:
10.1016/j.biochi.2021.09.005
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