Abstract
Proteasomes are responsible for protein turnover in eukaryotic cells, degrading short-lived species but also removing improperly folded or oxidatively damaged ones. Dysfunction of a proteasome results in gradual accumulation of misfolded/damaged proteins, leading to their aggregation. It has been postulated that proteasome activators may facilitate removal of such aggregation-prone proteins and thus prevent development of neurodegenerative disorders. However, the discovery of pharmacologically relevant compounds is hindered by insufficient structural understanding of the activation process. In this study we provide a model peptidic activator of human proteasome and analyze the structure-activity relationship within this novel scaffold. The binding mode of the activator at the relevant pocket within the proteasome has been determined by X-ray crystallography. This crystal structure provides an important basis for rational design of pharmacological compounds. Moreover, by providing a novel insight into the proteasome gating mechanism, our results allow the commonly accepted model of proteasome regulation to be revisited.
Highlights
The ubiquitin-proteasome system (UPS) is responsible for degradation of the majority of cytosolic proteins
In the latent 20S proteasome, access of polypeptides to the catalytic chamber is restricted by the N-termini of the α subunits, which form a kind of a gate[3]
The first amino acid was attached to the resin using a symmetrical anhydride or 1-(2-mesitylenesulfonyl)-3-nitro-1H-1,2,4-triazole/1-methylimidazole method, and the coupling efficiency was determined by measurement of absorbance of the resulting fulvene-piperidine adduct, at λ = 301 nm
Summary
The ubiquitin-proteasome system (UPS) is responsible for degradation of the majority of cytosolic proteins. In these constructs either (i) seven or eight residues of the C-terminal sequence of PA26 were substituted with the sequence of PAN’s C-terminus, holding the conserved HbYX motif (PDB: 3JTL/3IPM, respectively)[8, 13]; or (ii) only the penultimate Val residue of PA26 was exchanged into Phe (PDB: 3JSE) or Tyr (PDB: 3JRM)[8] In all these structures multiple contacts of the binding motifs with the proteasome intersubunit pockets were observed, resulting in the displacement of all seven Pro[17] clusters and the gate opening
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