Exploring the role of post-translational modifications in regulating α-synuclein interactions by studying the effects of phosphorylation on nanobody binding.
El Turk, Farah
De Genst, Erwin
Di Trani, Justin
Lashuel, Hilal A
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El Turk, F., De Genst, E., Guilliams, T., Fauvet, B., Hejjaoui, M., Di Trani, J., Chiki, A., et al. (2018). Exploring the role of post-translational modifications in regulating α-synuclein interactions by studying the effects of phosphorylation on nanobody binding.. Protein Sci, 27 (7), 1262-1274. https://doi.org/10.1002/pro.3412
Intracellular deposits of α-synuclein in the form of Lewy bodies are major hallmarks of Parkinson's disease (PD) and a range of related neurodegenerative disorders. Post-translational modifications (PTMs) of α-synuclein are increasingly thought to be major modulators of its structure, function, degradation and toxicity. Among these PTMs, phosphorylation near the C-terminus at S129 has emerged as a dominant pathogenic modification as it is consistently observed to occur within the brain and cerebrospinal fluid (CSF) of post-mortem PD patients, and its level appears to correlate with disease progression. Phosphorylation at the neighboring tyrosine residue Y125 has also been shown to protect against α-synuclein toxicity in a Drosophila model of PD. In the present study we address the potential roles of C-terminal phosphorylation in modulating the interaction of α-synuclein with other protein partners, using a single domain antibody fragment (NbSyn87) that binds to the C-terminal region of α-synuclein with nanomolar affinity. The results reveal that phosphorylation at S129 has negligible effect on the binding affinity of NbSyn87 to α-synuclein while phosphorylation at Y125, only four residues away, decreases the binding affinity by a factor of 400. These findings show that, despite the fact that α-synuclein is intrinsically disordered in solution, selective phosphorylation can modulate significantly its interactions with other molecules and suggest how this particular form of modification could play a key role in regulating the normal and aberrant function of α-synuclein.
Brain, Humans, Parkinson Disease, Tyrosine, Serine, Autopsy, Protein Processing, Post-Translational, Binding Sites, Protein Binding, Phosphorylation, alpha-Synuclein, Single-Domain Antibodies
Medical Research Council (G1002272)
External DOI: https://doi.org/10.1002/pro.3412
This record's URL: https://www.repository.cam.ac.uk/handle/1810/279744