Structures of PGAM5 Provide Insight into Active Site Plasticity and Multimeric Assembly

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Cell Biology

Background:

• PGAM5 is a mitochondrial protein involved in regulating oxidative stress, necroptosis, and autophagy.
• It functions as an atypical serine/threonine phosphatase.

Purpose of the Study:

• To elucidate the structural basis of PGAM5 activation and oligomerization.
• To provide detailed structural models of PGAM5, a key mitochondrial phosphatase implicated in various diseases.

Main Methods:

• X-ray crystallography to determine PGAM5 structures, including N-terminal regulatory sequences.
• Hydrogen-deuterium exchange mass spectrometry (HDX-MS) to study protein dynamics.
• Size-exclusion chromatography and analytical ultracentrifugation to analyze oligomeric states in solution.

Main Results:

• Crystal structures reveal PGAM5's structural plasticity, catalytic domain dimerization, and assembly into an active dodecamer.
• The N-terminal WDPNWD motif acts as a structural integrator, promoting dodecamer formation and allosteric activation.
• Active site plasticity was observed, enabling visualization of conformational changes in catalytic elements.

Conclusions:

• The N-terminal motif and dodecameric assembly are crucial for PGAM5's allosteric activation.
• Detailed structural models of PGAM5 offer insights into its function as a mitochondrial phosphatase.
• Understanding PGAM5 structure is vital for its association with diverse disease pathologies.