Enhancement of the Anti-Aggregation Activity of a Molecular Chaperone Using a Rationally Designed Post-Translational Modification

• Type: Article in International Scientific Journal
• Date: 2019

Authors

Lindstedt, PR (Author) Other; Aprile, FA (Author) Other; Matos, MJ (Author) FCUP; Perni, M (Author) Other; Bertoldo, JB (Author) Other; Bernardim, B (Author) Other; Peter, Q (Author) Other; Jimenez Oses, G (Author) Other; Knowles, TPJ (Author) Other; Dobson, CM (Author) Other; Corzana, F (Author) Other; Vendruscolo, M (Author) Other; Bernardes, GJL (Author) Other

Journal

Title: ACS Central Science

Vol. 5

Pages: 1417-1424

ISSN: 2374-7943

Publisher: American Chemical Society

Indexing

ISI Web of Knowledge - 5 Citations

Other information

Authenticus ID: P-00R-0NN

DOI: 10.1021/acscentsci.9b00467

Abstract (EN): Protein behavior is closely regulated by a plethora of post-translational modifications (PTMs). It is therefore desirable to develop approaches to design rational PTMs to modulate specific protein functions. Here, we report one such method, 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 alpha-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 alpha-synuclein aggregation and its associated toxicity in a Caenorhabditis elegans model of PD.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 8