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

Brooke M. Gardner, Dominic T. Castanzo, Saikat Chowdhury, Goran Stjepanovic, Matthew S. Stefely, James H. Hurley, Gabriel C. Lander and Andreas Martin ()
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Brooke M. Gardner: University of California, Berkeley
Dominic T. Castanzo: University of California, Berkeley
Saikat Chowdhury: The Scripps Research Institute
Goran Stjepanovic: University of California, Berkeley
Matthew S. Stefely: University of California, Berkeley
James H. Hurley: University of California, Berkeley
Gabriel C. Lander: The Scripps Research Institute
Andreas Martin: University of California, Berkeley

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract Pex1 and Pex6 form a heterohexameric motor essential for peroxisome biogenesis and function, and mutations in these AAA-ATPases cause most peroxisome-biogenesis disorders in humans. The tail-anchored protein Pex15 recruits Pex1/Pex6 to the peroxisomal membrane, where it performs an unknown function required for matrix-protein import. Here we determine that Pex1/Pex6 from S. cerevisiae is a protein translocase that unfolds Pex15 in a pore-loop-dependent and ATP-hydrolysis-dependent manner. Our structural studies of Pex15 in isolation and in complex with Pex1/Pex6 illustrate that Pex15 binds the N-terminal domains of Pex6, before its C-terminal disordered region engages with the pore loops of the motor, which then processively threads Pex15 through the central pore. Furthermore, Pex15 directly binds the cargo receptor Pex5, linking Pex1/Pex6 to other components of the peroxisomal import machinery. Our results thus support a role of Pex1/Pex6 in mechanical unfolding of peroxins or their extraction from the peroxisomal membrane during matrix-protein import.

Date: 2018
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DOI: 10.1038/s41467-017-02474-4

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