Structural and functional basis of protein phosphatase 5 substrate specificity

Area of Science:

• Molecular biology
• Biochemistry
• Structural biology

Background:

• Protein Phosphatase 5 (PP5) is a serine/threonine phosphatase that regulates cellular signaling pathways.
• PP5 interacts with heat shock protein 90 (Hsp90) and dephosphorylates its cochaperone Cdc37.
• This dephosphorylation is critical for activating Hsp90-dependent kinases, but the precise mechanism is unclear.

Purpose of the Study:

• To elucidate the structural basis of PP5-Cdc37 interaction.
• To understand how PP5 regulates Hsp90-dependent kinase activation and substrate release.
• To explore the therapeutic implications of PP5 activity in cancer.

Main Methods:

• Determined the crystal structure of PP5 catalytic domain bound to a Cdc37 phosphomimetic peptide.
• Utilized structure-based mutations to assess PP5 function in vivo.
• Investigated the effect of PP5 activity on Hsp90-inhibitor binding.

Main Results:

• The crystal structure revealed PP5 employs conserved phosphoprotein phosphatase (PPP) structural elements for substrate binding.
• Substrate specificity is determined by elements within the PP5 catalytic domain.
• PP5-mediated dephosphorylation is essential for releasing kinases and steroid hormone receptors from the Hsp90 complex.
• Altered PP5 activity modulated Hsp90 inhibitor binding, suggesting a role in therapeutic efficacy.

Conclusions:

• PP5 plays a crucial role in Hsp90 chaperone complex dynamics through Cdc37 dephosphorylation.
• The PP5 catalytic domain itself contributes to substrate specificity.
• Modulating PP5 activity offers a potential strategy to enhance the effectiveness of Hsp90 inhibitors in cancer treatment.