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Mycobacterium tuberculosis proteasomal ATPase Mpa has a β-grasp domain that hinders docking with the proteasome core
Yujie Wu1, Kuan Hu2,3, Defeng Li4
1Department of Biology, Southern University of Science and Technology, 1088 Xueyuan Road, Nanshan District, Shenzhen, 518055, China.
Abstract:
Mycobacterium tuberculosis (Mtb) has a proteasome system that is essential for its ability to cause lethal infections in mice. A key component of the system is the proteasomal adenosine triphosphatase (ATPase) Mpa, which captures, unfolds, and translocates protein substrates into the Mtb proteasome core particle for degradation. Here, we report the crystal structures of near full-length hexameric Mtb Mpa in apo and ADP-bound forms. Surprisingly, the structures revealed a ubiquitin-like β-grasp domain that precedes the proteasome-activating carboxyl terminus. This domain, which was only found in bacterial proteasomal ATPases, buries the carboxyl terminus of each protomer in the central channel of the hexamer and hinders the interaction of Mpa with the proteasome core protease. Thus, our work reveals the structure of a bacterial proteasomal ATPase in the hexameric form, and the structure finally explains why Mpa is unable to stimulate robust protein degradation in vitro in the absence of other, yet-to-be-identified co-factors.
Insights
The Mycobacterium tuberculosis proteasome ATPase Mpa has a unique structure that prevents it from activating protein degradation. This finding explains Mpa's limited in vitro activity and suggests the need for co-factors.
Area of Science:
- Structural biology
- Biochemistry
- Microbiology
Background:
- The Mycobacterium tuberculosis (Mtb) proteasome system is crucial for its pathogenicity.
- Mpa, a proteasomal ATPase, is essential for substrate processing by the Mtb proteasome.
Purpose of the Study:
- To determine the crystal structure of the hexameric Mtb Mpa.
- To elucidate the structural basis for Mpa's interaction with the Mtb proteasome core particle.
Main Methods:
- X-ray crystallography
- Analysis of apo and ADP-bound Mtb Mpa hexamers
Main Results:
- Revealed a novel ubiquitin-like β-grasp domain in Mpa.
- This domain obstructs the Mpa-proteasome core protease interaction.
- Observed that the β-grasp domain buries the carboxyl terminus of each protomer.
Conclusions:
- The Mtb Mpa structure explains its inability to robustly stimulate protein degradation in vitro.
- The findings suggest the requirement for unidentified co-factors for full Mpa function.
- Provides structural insights into bacterial proteasomal ATPase mechanisms.