Crystal structure of a low molecular weight activator Blm-pep with yeast 20S proteasome - insights into the enzyme activation mechanism

Julia Witkowska , Małgorzata Giżyńska , Przemysław Grudnik , Przemysław Golik , Przemysław Karpowicz , Artur Giełdoń , Grzegorz Dubin , Elżbieta Jankowska


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 andanalyze the structure-activity relationship within this novel scaffold. The binding mode of the activatorat 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.
Author Julia Witkowska (FCh / DBCh / LMCh)
Julia Witkowska,,
- Laboratory of Medical Chemistry
, Małgorzata Giżyńska (FCh / DBCh / LMCh)
Małgorzata Giżyńska,,
- Laboratory of Medical Chemistry
, Przemysław Grudnik
Przemysław Grudnik,,
, Przemysław Golik
Przemysław Golik,,
, Przemysław Karpowicz (FCh / DBCh / LMCh)
Przemysław Karpowicz ,,
- Laboratory of Medical Chemistry
, Artur Giełdoń (FCh / DTCh / LSP)
Artur Giełdoń,,
- Laboratory of Simulation of Polymers
, Grzegorz Dubin
Grzegorz Dubin,,
, Elżbieta Jankowska (FCh / DBCh / LMCh)
Elżbieta Jankowska,,
- Laboratory of Medical Chemistry
Other language title versions
Journal seriesScientific Reports, ISSN 2045-2322, (A 40 pkt)
Issue year2017
Publication size in sheets0.5
ASJC Classification1000 Multidisciplinary
Languageen angielski
LicenseJournal (articles only); published final; Uznanie Autorstwa (CC-BY); with publication
Score (nominal)40
ScoreMinisterial score = 40.0, 01-04-2019, ArticleFromJournal
Ministerial score (2013-2016) = 40.0, 01-04-2019, ArticleFromJournal
Publication indicators WoS Citations = 4; Scopus SNIP (Source Normalised Impact per Paper): 2016 = 1.401; WoS Impact Factor: 2017 = 4.122 (2) - 2017=4.609 (5)
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* presented citation count is obtained through Internet information analysis and it is close to the number calculated by the Publish or Perish system.