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

Nature Microbiology
Stanley C XieLeann Tilley

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 dynami...Continue Reading

References

Dec 5, 1993·Journal of Molecular Biology·A Sali, T L Blundell
Feb 1, 1996·Journal of Molecular Graphics·W HumphreyK Schulten
Sep 1, 1996·Protein Science : a Publication of the Protein Society·J A Boice, R Fairman
Dec 24, 1997·Nature·J R KnowltonC P Hill
Apr 18, 1998·Proceedings of the National Academy of Sciences of the United States of America·Z ZhangM Rechsteiner
May 23, 1998·The Journal of Biological Chemistry·Z ZhangM Rechsteiner
May 9, 2000·The Journal of Biological Chemistry·N TanahashiK Tanaka
Jun 29, 2000·Annual Review of Biochemistry·D VogesW Baumeister
Nov 4, 2000·Nature Structural Biology·M GrollD Finley
May 24, 2001·Biophysical Journal·D I SvergunM H Koch
Aug 23, 2001·Proceedings of the National Academy of Sciences of the United States of America·N A BakerJ A McCammon
Feb 14, 2002·International Journal for Parasitology·Manoj T DuraisinghAlan F Cowman
May 29, 2002·The EMBO Journal·Paolo CascioAlfred L Goldberg
Aug 28, 2003·The EMBO Journal·Andreas FörsterChristopher P Hill
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
Oct 14, 2005·Journal of Computational Chemistry·James C PhillipsKlaus Schulten
Aug 25, 2006·Acta Crystallographica. Section D, Biological Crystallography·Kevin Cowtan
Oct 2, 2007·Protein Science : a Publication of the Protein Society·Lisa D CabritaStephen P Bottomley
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Wolfgang Kabsch
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsPeter H Zwart
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·Kevin Cowtan
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
Nov 26, 2010·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Jie LiXuejun Wang
Jan 22, 2011·Molecular and Biochemical Parasitology·Suresh M GanesanAkhil B Vaidya
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·Martyn D WinnKeith S Wilson
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·Philip R Evans
Nov 1, 2011·Nature Structural & Molecular Biology·Geng TianDaniel Finley
Apr 17, 2012·Molecular Cell·Paula C A da FonsecaEdward P Morris
Apr 17, 2012·Acta Crystallographica. Section D, Biological Crystallography·Jeffrey J HeaddPaul D Adams
Feb 5, 2013·Biochemical and Biophysical Research Communications·Masaaki SugiyamaKoichi Kato
Jun 12, 2013·Nucleic Acids Research·Daniel W A BuchanDavid T Jones
Jun 26, 2013·Acta Crystallographica. Section D, Biological Crystallography·Philip R Evans, Garib N Murshudov

❮ Previous
Next ❯

Citations

Nov 5, 2019·Expert Opinion on Therapeutic Targets·Stanley C XieLeann Tilley
Feb 26, 2020·Proceedings of the National Academy of Sciences of the United States of America·Enrico RennellaLewis E Kay
Feb 11, 2021·Biomolecules·Paolo Cascio
Mar 3, 2021·Trends in Parasitology·Tuo YangUNKNOWN Malaria Drug Accelerator Consortium
Jun 6, 2020·The Journal of Physical Chemistry. B·Arjun SahaArieh Warshel
May 11, 2021·ACS Infectious Diseases·Melissa R Rosenthal, Caroline L Ng
Jun 3, 2021·Proceedings of the National Academy of Sciences of the United States of America·Arjun Saha, Arieh Warshel
Aug 17, 2021·Current Opinion in Structural Biology·Chenyi LiaoGuohui Li
Sep 23, 2021·Proceedings of the National Academy of Sciences of the United States of America·Stanley C XieLeann Tilley

❮ Previous
Next ❯

Methods Mentioned

BETA
electrophoresis
X-ray
flow cytometry
PCR
transfection
gel filtration
size-exclusion chromatography

Software Mentioned

HYDROPRO
BUCCANEER
MODELLER
COOT
real
. analyse
PyMOL
FlowJo
GASBOR
NAMD

Related Concepts

Related Feeds

Antimalarial Agents (ASM)

Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.

Antimalarial Agents

Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.