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Angew Chem Int Ed Engl. 2015 Jun 22;54(26):7529-33. doi: 10.1002/anie.201501011. Epub 2015 May 8.

Structural effects of multiple pathogenic mutations suggest a model for the initiation of misfolding of the prion protein.

Author information

1
National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bengaluru 560065 (India).
2
National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bengaluru 560065 (India). jayant@ncbs.res.in.

Abstract

A molecular understanding of the prion diseases requires delineation of the origin of misfolding of the prion protein (PrP). An understanding of how different disease-linked mutations affect the structure and dynamics of native monomeric PrP can provide a clue about how misfolding commences. In this study, hydrogen-deuterium exchange mass spectrometry was used to show that several disease-linked mutant variants, which are thermodynamically destabilized, share a common structural perturbation in their native states: helix 1 is destabilized to an extent that correlates well with the destabilization of the native protein. The mutant variants misfold and form oligomers faster than does the wild-type protein, at rates that increase exponentially with the extent to which helix 1 is destabilized in the native protein. It appears, therefore, that the loss of helix 1 structure marks the beginning of PrP misfolding and oligomerization.

KEYWORDS:

hydrogen-deuterium exchange; mass spectrometry; misfolding; pathogenic mutations; prion proteins

PMID:
25959220
DOI:
10.1002/anie.201501011
[Indexed for MEDLINE]

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