Mycobacterium tuberculosis protein tyrosine phosphatase PtpB structure reveals a diverged fold and a buried active...

Area of Science:

• Microbiology
• Structural Biology
• Biochemistry

Background:

• Intracellular pathogenic bacteria, such as Mycobacterium tuberculosis, can manipulate host cell signaling pathways to establish infection.
• Mycobacterium tuberculosis protein tyrosine phosphatases (PTPs), PtpA and PtpB, are implicated in interfering with host cell signals, but their mechanisms remain unclear.

Purpose of the Study:

• To elucidate the structural basis of PtpB's function and substrate recognition.
• To understand the regulatory mechanisms and unique structural features of Mycobacterium tuberculosis PTPs.

Main Methods:

• Determined the 1.7 Å resolution crystal structure of PtpB in complex with phosphate.
• Performed biochemical studies to investigate enzyme activity and stability.

Main Results:

• PtpB adopts a simplified PTP fold with unique features, including a disordered acidic loop and a flexible two-helix lid covering the active site, characteristic of mycobacterial orthologs.
• The lid structure may protect the phosphatase from oxidative inactivation through substrate mimicry.
• Significant structural variations, including insertions and deletions, were observed outside the active site module.

Conclusions:

• PtpB possesses unique structural adaptations potentially related to host-pathogen interactions and survival.
• The PTP family exhibits significant structural plasticity, particularly in mycobacteria, suggesting evolutionary pressures driving diversification beyond the conserved active site.