6muv Citations

The structure of the PA28-20S proteasome complex from Plasmodium falciparum and implications for proteostasis.

Abstract

The activity of the proteasome 20S catalytic core is regulated by protein complexes that bind to one or both ends. The PA28 regulator stimulates 20S proteasome peptidase activity in vitro, but its role in vivo remains unclear. Here, we show that genetic deletion of the PA28 regulator from Plasmodium falciparum (Pf) renders malaria parasites more sensitive to the antimalarial drug dihydroartemisinin, indicating that PA28 may play a role in protection against proteotoxic stress. The crystal structure of PfPA28 reveals a bell-shaped molecule with an inner pore that has a strong segregation of charges. Small-angle X-ray scattering shows that disordered loops, which are not resolved in the crystal structure, extend from the PfPA28 heptamer and surround the pore. Using single particle cryo-electron microscopy, we solved the structure of Pf20S in complex with one and two regulatory PfPA28 caps at resolutions of 3.9 and 3.8 Å, respectively. PfPA28 binds Pf20S asymmetrically, strongly engaging subunits on only one side of the core. PfPA28 undergoes rigid body motions relative to Pf20S. Molecular dynamics simulations support conformational flexibility and a leaky interface. We propose lateral transfer of short peptides through the dynamic interface as a mechanism facilitating the release of proteasome degradation products.

Reviews - 6muv mentioned but not cited (1)

Articles - 6muv mentioned but not cited (1)



Reviews citing this publication (4)

  1. MalDA, Accelerating Malaria Drug Discovery. Yang T, Ottilie S, Istvan ES, Godinez-Macias KP, Lukens AK, Baragaña B, Campo B, Walpole C, Niles JC, Chibale K, Dechering KJ, Llinás M, Lee MCS, Kato N, Wyllie S, McNamara CW, Gamo FJ, Burrows J, Fidock DA, Goldberg DE, Gilbert IH, Wirth DF, Winzeler EA, Malaria Drug Accelerator Consortium. Trends Parasitol 37 493-507 (2021)
  2. PA28γ: New Insights on an Ancient Proteasome Activator. Cascio P. Biomolecules 11 228 (2021)
  3. Expanding the role of proteasome homeostasis in Parkinson's disease: beyond protein breakdown. Bi M, Du X, Jiao Q, Chen X, Jiang H. Cell Death Dis 12 154 (2021)
  4. Structure, Function, and Allosteric Regulation of the 20S Proteasome by the 11S/PA28 Family of Proteasome Activators. Thomas T, Salcedo-Tacuma D, Smith DM. Biomolecules 13 1326 (2023)

Articles citing this publication (15)