Abstract
Recent studies suggest that Tyr-39 might play a critical role for both the normal function and the pathological dysfunction of α-synuclein (αS), an intrinsically disordered protein involved in Parkinson’s disease. We perform here a comparative analysis between the structural features of human αS and its Y39A, Y39F, and Y39L variants. By the combined application of site-directed mutagenesis, biophysical techniques, and enhanced sampling molecular simulations, we show that removing aromatic functionality at position 39 of monomeric αS leads to protein variants populating more compact conformations, conserving its disordered nature and secondary structure propensities. Contrasting with the subtle changes induced by mutations on the protein structure, removing aromaticity at position 39 impacts strongly on the interaction of αS with the potent amyloid inhibitor phthalocyanine tetrasulfonate (PcTS). Our findings further support the role of Tyr-39 in forming essential inter and intramolecular contacts that might have important repercussions for the function and the dysfunction of αS.
Highlights
Neurodegenerative disorders such as Parkinson’s and Alzheimer’s are among the human diseases associated with the self-assembly of polypeptides into amyloid structures [1,2]
The structural features of the monomeric wild-type, Y39F, Y39L, and Y39A αS species were investigated by circular dichroism (CD), NMR spectroscopy, along with REST2 simulations [30]
We investigated the importance of aromaticity at position 39 in αS through the analysis of the impact of Y39F, Y39L, and Y39A mutations on the structural properties of its monomeric state and its interaction with the anti-amyloid agent phthalocyanine tetrasulfonate (PcTS)
Summary
Neurodegenerative disorders such as Parkinson’s and Alzheimer’s are among the human diseases associated with the self-assembly of polypeptides into amyloid structures [1,2]. Toward the design of effective therapeutics to combat these diseases, one of the major unanswered questions of protein aggregation is the propensity of particular primary sequences to aggregate [1,2] These relevant regions are usually known as aggregation “hot spots”, and their study becomes critical to identify determinants governing protein aggregation and to reveal specific interactions that must be disrupted to prevent amyloid assembly. This knowledge can in turn be used for therapeutic intervention to target the aggregation pathway of these proteins and its associated toxicity [3]. Aromatic groups are a frequent feature in these inhibitors [6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24]; the ability of these molecules to impair amyloid formation might be mediated by π−π interactions with aromatic residues in specific regions of the protein sequence
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