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Proc Natl Acad Sci U S A. 2015 Jul 28;112(30):E4017-25. doi: 10.1073/pnas.1500257112. Epub 2015 Jul 13.

Unique double-ring structure of the peroxisomal Pex1/Pex6 ATPase complex revealed by cryo-electron microscopy.

Author information

1
Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115; Department of Cell Biology, Harvard Medical School, Boston, MA 02115;
2
Department of Biochemistry, University of Washington, Seattle, WA 98195; Graduate Program in Biological Physics, Structure and Design, University of Washington, Seattle, WA 98195;
3
Department of Biochemistry and Molecular Biology, The University of Texas Medical School, Houston, TX 77054;
4
Department of Biochemistry, University of Washington, Seattle, WA 98195; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195.
5
Department of Biochemistry, University of Washington, Seattle, WA 98195;
6
Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115; Department of Cell Biology, Harvard Medical School, Boston, MA 02115; tom_rapoport@hms.harvard.edu twalz@hms.harvard.edu.

Abstract

Members of the AAA family of ATPases assemble into hexameric double rings and perform vital functions, yet their molecular mechanisms remain poorly understood. Here, we report structures of the Pex1/Pex6 complex; mutations in these proteins frequently cause peroxisomal diseases. The structures were determined in the presence of different nucleotides by cryo-electron microscopy. Models were generated using a computational approach that combines Monte Carlo placement of structurally homologous domains into density maps with energy minimization and refinement protocols. Pex1 and Pex6 alternate in an unprecedented hexameric double ring. Each protein has two N-terminal domains, N1 and N2, structurally related to the single N domains in p97 and N-ethylmaleimide sensitive factor (NSF); N1 of Pex1 is mobile, but the others are packed against the double ring. The N-terminal ATPase domains are inactive, forming a symmetric D1 ring, whereas the C-terminal domains are active, likely in different nucleotide states, and form an asymmetric D2 ring. These results suggest how subunit activity is coordinated and indicate striking similarities between Pex1/Pex6 and p97, supporting the hypothesis that the Pex1/Pex6 complex has a role in peroxisomal protein import analogous to p97 in ER-associated protein degradation.

KEYWORDS:

AAA ATPase; Pex1; Pex6; cryo-electron microscopy; peroxisome

PMID:
26170309
PMCID:
PMC4522808
DOI:
10.1073/pnas.1500257112
[Indexed for MEDLINE]
Free PMC Article

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