The peroxisomal AAA-ATPase Pex1/Pex6 unfolds substrates by processive threading.

Area of Science:

• Cell Biology
• Molecular Motors
• Protein Trafficking

Background:

• Peroxisome biogenesis and function rely on the Pex1/Pex6 motor complex.
• Mutations in Pex1/Pex6 cause human peroxisome-biogenesis disorders.
• Pex15 recruits Pex1/Pex6 to the peroxisomal membrane for matrix-protein import.

Purpose of the Study:

• To elucidate the function of Pex1/Pex6 in peroxisome matrix-protein import.
• To determine the mechanism by which Pex1/Pex6 interacts with and processes Pex15.
• To understand the role of Pex15 in linking Pex1/Pex6 to other import components.

Main Methods:

• Structural studies of Pex15 and its complex with Pex1/Pex6.
• Biochemical assays to determine ATP hydrolysis dependence.
• Analysis of protein-protein interactions.

Main Results:

• Pex1/Pex6 acts as a protein translocase, unfolding Pex15 in an ATP-dependent manner.
• Pex15 binds to Pex6 N-terminal domains and engages with motor pore loops for threading.
• Pex15 directly interacts with the Pex5 cargo receptor, linking the motor to the import machinery.

Conclusions:

• Pex1/Pex6 mechanically unfolds Pex15 during peroxisomal matrix-protein import.
• This unfolding mechanism is critical for peroxisome function and may be relevant to disease.
• The findings reveal a novel role for AAA-ATPases in protein translocation and unfolding.