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Molecular mechanism of prion protein oligomerization at atomic resolution

27 August 2013. Transmissible spongiform encephalopathies, also known as prion diseases, severly affect the brain and nervous system. Prion diseases include Creutzfeldt–Jakob disease in humans and bovine spongiform encephalopathy (BSE, commonly known as "mad cow disease") in cattle. Unlike other kinds of infectious disease which are spread by microbes, the infectious agent in this case is a specific protein called prion protein. Misfolding of the normal cellular isoform of the prion protein (PrPC) to the abnormal aggregated isoform (PrPSc) is the central hallmark of transmissible prion diseases.

Despite the crucial role of oligomers during prion protein pathogenesis the molecular mechanism of their formation has remained largely elusive. A 2D time-resolved NMR study led by Harald Schwalbe at the Goethe University Frankfurt has now characterized the oligomerization kinetics with unprecedented site-specificity. 

Such site-resolved information regarding the pathway PrP monomers follow to give rise to macromolecular assemblies is urgently required as a basis to devise successful small-molecule-based approaches preventing oligomerization.

Kai Schlepckow and Harald Schwalbe overcame the limited structural resolution in previous mechanistic studies by applying time-resolved NMR spectroscopy and characterize the oligomerization kinetics of recombinant murine PrP (mPrP) at single-residue level.Based on their findings the scientists propose a model for prion protein oligomerization and self-assembly.

The study, published recently in the journal Angewandte Chemie International Edition, yields unique insight into the distribution of initially formed oligomers and how they interact to form higher-order assemblies. The analysis reveals significant oligomer polydispersity which is in general accordance with simulations of monomer-loss kinetics under conditions where oligomerization is not unfolding-limited. The data allow the scientists to determine the effective concentrations of distinct ensembles of oligomeric species, gaining access to important parameters such as size, concentration, and stabilizing intermolecular interactions of oligomeric species which may constitute key intermediates during PrP pathogenesis. They are now in the position to investigate the effect of disease-associated single-point mutations on the kinetics of oligomer formation, which will be subject of further studies. The outlined approach of analyzing the sequence-dependent monomer-loss kinetics should be broadly applicable to a wide range of proteins implicated in neurodegenerative diseases and provide long-sought mechanistic insight into how these proteins self-assemble into oligomeric and fibrillar structures. More ....


Harald Schwalbe
Institute of Organic Chemistry and Chemical Biology
Riedberg Campus
Goethe Univerity Frankfurt
Tel.: +49 69 798-29130


Kai Schlepckow & Harald Schwalbe (2013) Molecular Mechanism of Prion Protein Oligomerization at Atomic Resolution. Angew Chem Int Edit. Published online 9 August 2013, DOI 10.1002/anie.201305184. Link to full paper