Exploring the role of post-translational modifications in regulating α-synuclein interactions by studying the effects of phosphorylation on nanobody binding.
View / Open Files
Authors
El Turk, Farah
De Genst, Erwin
Guilliams, Tim
Fauvet, Bruno
Hejjaoui, Mirva
Di Trani, Justin
Chiki, Anass
Mittermaier, Anthony
Lashuel, Hilal A
Dobson, Christopher
Publication Date
2018-07Journal Title
Protein Sci
ISSN
0961-8368
Publisher
Wiley
Volume
27
Issue
7
Pages
1262-1274
Language
eng
Type
Article
This Version
AM
Physical Medium
Print
Metadata
Show full item recordCitation
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
Abstract
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.
Keywords
Brain, Humans, Parkinson Disease, Tyrosine, Serine, Autopsy, Protein Processing, Post-Translational, Binding Sites, Protein Binding, Phosphorylation, alpha-Synuclein, Single-Domain Antibodies
Sponsorship
Medical Research Council (G1002272)
Identifiers
External DOI: https://doi.org/10.1002/pro.3412
This record's URL: https://www.repository.cam.ac.uk/handle/1810/279744
Rights
Licence:
http://www.rioxx.net/licenses/all-rights-reserved
Statistics
Total file downloads (since January 2020). For more information on metrics see the
IRUS guide.