8D6W

Structure of the Mycobacterium tuberculosis 20S proteasome bound to the C-terminal GQYL motif of the ADP-bound Mpa ATPase

Summary for 8D6W

• Entry DOI: 10.2210/pdb8d6w/pdb
• EMDB information: 27224
• Descriptor: Proteasome subunit alpha, Proteasome subunit beta, Proteasome-associated ATPase (3 entities in total)
• Functional Keywords: mpa, proteasome, antimicrobial protein
• Biological source: Mycobacterium tuberculosis; More
• Total number of polymer chains: 35
• Total formula weight: 804759.32

Authors

Xiao, X.,Li, H. (deposition date: 2022-06-06, release date: 2022-08-03, Last modification date: 2024-06-12)

Primary citation

Xiao, X.,Feng, X.,Yoo, J.H.,Kovach, A.,Darwin, K.H.,Li, H.
The beta-Grasp Domain of Proteasomal ATPase Mpa Makes Critical Contacts with the Mycobacterium tuberculosis 20S Core Particle to Facilitate Degradation.
Msphere, 7:e0027422-e0027422, 2022

PubMed Abstract: Mycobacterium tuberculosis possesses a Pup-proteasome system analogous to the eukaryotic ubiquitin-proteasome pathway. We have previously shown that the hexameric mycobacterial proteasome ATPase (Mpa) recruits pupylated protein substrates via interactions between amino-terminal coiled-coils in Mpa monomers and the degradation tag Pup. However, it is unclear how Mpa rings interact with a proteasome due to the presence of a carboxyl-terminal β-grasp domain unique to Mpa homologues that makes the interaction highly unstable. Here, we describe newly identified critical interactions between Mpa and 20S core proteasomes. Interestingly, the Mpa C-terminal GQYL motif binds the 20S core particle activation pocket differently than the same motif of the ATP-independent proteasome accessory factor PafE. We further found that the β-hairpin of the Mpa β-grasp domain interacts variably with the H0 helix on top of the 20S core particle via a series of ionic and hydrogen-bond interactions. Individually mutating several involved residues reduced Mpa-mediated protein degradation both and . The Pup-proteasome system in Mycobacterium tuberculosis is critical for this species to cause lethal infections in mice. Investigating the molecular mechanism of how the Mpa ATPase recruits and unfolds pupylated substrates to the 20S proteasomal core particle for degradation will be essential to fully understand how degradation is regulated, and the structural information we report may be useful for the development of new tuberculosis chemotherapies.

PubMed: 35993699
DOI: 10.1128/msphere.00274-22

Experimental method

ELECTRON MICROSCOPY (3 Å)