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Natively unfolded proteins, aggregation and disease

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Title Natively unfolded proteins, aggregation and disease
Period 01 / 2007 - 01 / 2012
Status Current
Research number OND1315011
Data Supplier Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)

Abstract

This application concerns an intriguing class of natively unfolded proteins, whose existence questions one of the cornerstones in protein biology, chemistry and physics, that is, the structure?function paradigm. This proposal is built around two themes: First, what do we require to study unfolded proteins with atomic resolution? The main bottle neck here is the limited dispersion of chemical shift, which yields highly overlapped spectra. This will demand innovative development of NMR methodology suitable to deal with the overlap problem, especially for longer polypeptide chains. In the first part of this proposal I propose to establish NMR experiments and protocols for the sequential resonance assignment, and biophysical characterization of unfolded proteins. Second, is it possible to investigate a protein - which is known to aggregate - under equilibrium conditions and identify regions of the polypeptide chain that undergo reversible structural transitions to sparsely populated, but aggregation-prone conformations? For this we will study the neuronal tau protein in response to various conditions that lead to fibril formation; the addition of polyanions, mutations in two hexapeptides known to contain beta-propensity, and (hyper)phosphorylation. It is hoped that these studies contribute to an increased understanding of natively unfolded proteins, their biological function, and the abberant behaviour of polypeptides to misfold and aggregate. Keywords: NMR Spectroscopy, intrinsic disorder, aggregation, neuronal tau protein, Alzheimer's disease

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Project leader Dr. F.A.A. Mulder

Classification

D13200 Macromolecular chemistry, polymer chemistry
D21200 Biophysics, clinical physics
D21300 Biochemistry
D23100 Pathology, pathological anatomy

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