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Microsecond sub-domain motions and the folding and misfolding of the mouse prion protein

Rama Reddy Goluguri1, Sreemantee Sen1, Jayant Udgaonkar1,2

  • 1National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bengaluru, India.

Elife
|April 27, 2019
PubMed

Insights

Understanding protein aggregation requires studying native protein dynamics. This research used photoinduced electron transfer coupled to fluorescence correlation spectroscopy (PET-FCS) to reveal how native state fluctuations initiate protein aggregation.

Area of Science:

  • Biochemistry
  • Biophysics
  • Structural Biology

Background:

  • Protein aggregation is implicated in various diseases.
  • Partially unfolded protein conformations, arising from native protein fluctuations, are believed to initiate aggregation.
  • Characterizing these dynamics under native-like conditions remains challenging.

Purpose of the Study:

  • To investigate the conformational dynamics of the full-length mouse prion protein under native conditions.
  • To elucidate the role of native state fluctuations in the initiation of protein aggregation.

Main Methods:

  • Utilized photoinduced electron transfer coupled to fluorescence correlation spectroscopy (PET-FCS).
  • Employed microsecond mixing experiments to analyze the slowest fluctuations.
  • Studied the effects of salt addition on protein dynamics.

Main Results:

  • Identified two distinct timescales of fluctuations within the native state ensemble.
  • Associated the slowest fluctuations with the folding from an unfolded to an intermediate state.
  • Observed an enhancement in the timescale of core protein fluctuations upon salt addition, a known aggregation trigger.

Conclusions:

  • Native state dynamics play a crucial role in initiating protein aggregation.
  • PET-FCS is a powerful technique for characterizing protein conformational fluctuations under native conditions.
  • Understanding these dynamics offers insights into disease mechanisms and potential therapeutic targets.
Keywords:
Native state dynamicsPET-FCSdry molten globulemicrosecond fluctuationsmicrosecond mixingmolecular biophysicsmouse prion proteinnonestructural biology

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