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Novel use of EPR spectroscopy to study in vivo protein structure - Bruker white paper

Novel use of EPR spectroscopy to study in vivo protein structure: α-synuclein is a protein found abundantly throughout the brain. It is present mainly at the neuron ends where it is thought to play a role in ensuring the supply of synaptic vesicles in presynaptic terminals, which are required for the release of neurotransmitters to relay signals between neurons. It is critical for normal brain function.

APPLICATIONS & TECHNIQUES

Proteins
& Nucleic Acids

The Resonance (2016); News Medical – Life Sciences
& Medicine (April 15, 2016)

Bruker
Article: Novel use of
EPR spectroscopy to study in vivo protein structure

LIFE
SCIENCES & MEDICINE

April 15, 2016

EPR
Spectroscopy Reveals in vivo Structure of α-synuclein Protein

α-synuclein retains a disordered monomeric
form even within living mammalian cells

For many years, there has been controversy surrounding the structure of
α-synuclein. This protein is classed as an intrinsically disordered protein
since it was found not to have the precise 3D folded structure usually
associated with proteins. However, it has only been viewed in vitro and
some researchers reported that α-synuclein forms helical tetramers under
physiological conditions. Consequently, it was proposed that α-synuclein may
have a precise conformation in vivo that is lost on extraction.

There is particular interest in the α-synuclein protein since it was
discovered to be a key component of the amyloid plaques that develop in the
brain in Parkinson’s disease. Although the precise function of α-synuclein has
yet to be fully elucidated, it is known to play a role in neurotransmission and
be vital for normal brain function. It is therefore not surprising that
α-synuclein is found throughout the brain.

What is surprising is that in Parkinson’s disease it only aggregates to
form the characteristic plaques in very specific distinct areas of the brain.
It was thought that the protein must therefore undergo conformational changes
according to its immediate environment. The difficulties in viewing the protein
in living mammalian cells have meant that such theories regarding the in
vivo structure of α-synuclein could not be verified.

Researchers have now, for the first time, succeeded in visualizing the
atomic structure of α-synuclein in living mammalian cells^1,2. They
achieved this by utilizing in-cell nuclear magnetic resonance (NMR) imaging
with a similar technique that was developed to measure radicals and metal
complexes — electron paramagnetic resonance (EPR) spectroscopy.

Like NMR, EPR images are achieved from the energy released during the
transition from excited to relaxed molecular states. The difference being that
in EPR it is the electrons that are made to spin, rather than atomic nuclei.
EPR has recently started to be used in biological applications, for example, in
the study of the dynamic organization of lipids in biological membranes³,
but this is the first time it has been used in the determination of protein
structure.

In five types of living mammalian cells the α-synuclein protein was
present as a disordered, highly dynamic monomer. Major conformational changes
were not observed between different intracellular environments.

The novel use of EPR spectroscopy has started to resolve the debate
surrounding the in vivo conformation of α-synuclein. It has showed that
proteins of intrinsic structural disorder do exist within mammalian cells under
physiological cell conditions.

This research paves the way for further research into α-synuclein and
the cause of Parkinsonian amyloid plaques, which may allow curative treatments
to be developed in the future.

References

1. Theillet FX, et al. Structural disorder of
   monomeric α-synuclein persists in mammalian cells. Nature 2016;
   doi:10.1038/nature16531.
2. Alderson TA and Bax AD. Parkinson’s Disease.
   Disorder in the court. Nature 2016; doi:10.1038/nature16871.
3. Yashroy RC. Magnetic resonance studies of
   dynamic organisation of lipids in chloroplast membranes. Journal of
   Biosciences 1990;15(4):281.

 

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