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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • ATPases Associated with Diverse Cellular Activities / metabolism*
  • Adenosine Triphosphatases / antagonists & inhibitors
  • Membrane Proteins / metabolism*
  • Peroxisomes / enzymology*
  • Phosphoproteins / metabolism*
  • Protein Conformation
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins / metabolism*

Substances

  • Membrane Proteins
  • PEX15 protein, S cerevisiae
  • Phosphoproteins
  • Saccharomyces cerevisiae Proteins
  • Adenosine Triphosphatases
  • ATPases Associated with Diverse Cellular Activities
  • PEX1 protein, S cerevisiae
  • PEX6 protein, S cerevisiae