Reference: Gardner BM, et al. (2018) The peroxisomal AAA-ATPase Pex1/Pex6 unfolds substrates by processive threading. Nat Commun 9(1):135

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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.

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Journal Article | Research Support, N.I.H., Extramural | Research Support, Non-U.S. Gov't | Research Support, U.S. Gov't, Non-P.H.S.
Authors
Gardner BM, Castanzo DT, Chowdhury S, Stjepanovic G, Stefely MS, Hurley JH, Lander GC, Martin A
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