Disordered Motifs and Domains in Cell Control
Poster Session I
5-POS
Board 5
Residue-level Insights into α-synuclein Aggregation
Ciara Kyne
, Peter B. Crowley.
School of Chemistry, National University of Ireland Galway, Galway, Ireland.
The structural properties of intrinsically disordered proteins (IDP’s) give them unique binding
abilities.
1
For example, IDP’s have increased conformational freedom and large “capture radii”,
allowing them to rapidly encounter partner proteins.
2
IDP flexibility can also facilitate induced
folding upon binding.
1,2
Such disparate binding abilities allow IDP’s to interact with a number of
partners, making them important regulators of macromolecular assemblies in cells.
1,3
Erroneous
IDP interactions therefore have drastic consequences
in vivo
. For example, IDP-mediated
aggregates (amyloids) are pathological hallmarks of many neurodegenerative
diseases.
3
Although the molecular-level mechanisms of amyloid formation remain poorly
understood, evidence suggests that the process of IDP aggregation in vitro is similar to that
observed in biology.
3
Thus, studies of IDP aggregation under simplified conditions will improve
our understanding of amyloid formation in cells. Similarly, studies of IDP interactions with
ligands that promote or inhibit aggregation can reveal sites of importance in the aggregation
process.
4
α-synuclein (α-syn) is an IDP that forms the major component of cytoplasmic amyloids
associated with Parkinson’s disease, multiple system atrophy and dementia.
3
Here, we describe
the NMR characterization of α-syn’s interaction with a known inhibitor of α-syn aggregation.
The interaction between α-syn and a macrocyclic molecule will also be discussed. The
implications for α-syn self-association will be addressed.
1. V. N. Uversky,
FEBS Lett.
2013, 587, 1891.
2. B. A. Shoemaker et al.,
Proc. Natl. Acad. Sci. U.S.A.
2000, 97, 8868.
3. F-X. Theillet et al.,
Chem. Rev.
2014, 114, in press.
4. E. Akoury et al.,
J. Am. Chem. Soc.
2013, 135, 2853.
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