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Nat Commun. 2018 Jan 10;9(1):135. doi: 10.1038/s41467-017-02474-4.

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

Author information

1
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, 94720, USA.
2
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA.
3
Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA.
4
California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, 94720, USA.
5
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, 94720, USA. a.martin@berkeley.edu.
6
California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, 94720, USA. a.martin@berkeley.edu.
7
Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA, 94720, USA. a.martin@berkeley.edu.

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.

PMID:
29321502
PMCID:
PMC5762779
DOI:
10.1038/s41467-017-02474-4
[Indexed for MEDLINE]
Free PMC Article

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