Enhancement of the Anti-Aggregation Activity of a Molecular Chaperone Using a Rationally Designed Post-Translational Modification.
Lindstedt, Philip R
Matos, Maria J
Bertoldo, Jean B
ACS central science
American Chemical Society
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Lindstedt, P. R., Aprile, F., Matos, M. J., Perni, M., Bertoldo, J. B., Bernardim de Souza, B., Peter, Q., et al. (2019). Enhancement of the Anti-Aggregation Activity of a Molecular Chaperone Using a Rationally Designed Post-Translational Modification.. ACS central science, 5 (8), 1417-1424. https://doi.org/10.1021/acscentsci.9b00467
Protein behaviour is scrupulously regulated by a plethora of post-translational modifications (PTMs). It is therefore desirable to develop methods to design rational PTMs to modulate specific protein functions. Here, we report such an approach and we illustrate its successful implementation by potentiating the anti-aggregation activity of a molecular chaperone. Molecular chaperones are a multifaceted class of proteins essential to protein homeostasis, and one of their major functions is to combat protein misfolding and aggregation, a phenomenon linked to a number of human disorders. In this work, we conjugated a small molecule inhibitor of the aggregation of -synuclein, a process associated with Parkinson’s disease (PD), to a specific cysteine residue on human Hsp70, a molecular chaperone with five free cysteines. We show that this regioselective conjugation augments in vitro the anti-aggregation activity of Hsp70 in a synergistic manner. This Hsp70 variant also displays in vivo an enhanced suppression of -synuclein aggregation and its associated toxicity in a C. elegans model of PD.
Royal Society (URF\R\180019)
Alzheimer's Society (317 (AS-SF-16-003))
External DOI: https://doi.org/10.1021/acscentsci.9b00467
This record's URL: https://www.repository.cam.ac.uk/handle/1810/294828
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