Disordered Motifs and Domains in Cell Control - October 11-15, 2014

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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