Atypical AAA+ Subunit Packing Creates an Expanded Cavity for Disaggregation by the Protein-Remodeling Factor Hsp104

Petra Wendler; James Shorter; Celia Plisson; Anil G. Cashikar; Susan Lindquist; Helen R. Saibil

doi:10.1016/j.cell.2007.10.047

Atypical AAA+ Subunit Packing Creates an Expanded Cavity for Disaggregation by the Protein-Remodeling Factor Hsp104

Petra Wendler, James Shorter, Celia Plisson, Anil G. Cashikar, Susan Lindquist, Helen R. Saibil

Research output: Contribution to journal › Article › peer-review

104 Scopus citations

Abstract

Hsp104, a yeast protein-remodeling factor of the AAA+ (ATPases associated with various cellular activities) superfamily, and its homologs in bacteria and plants mediate cell recovery after severe stress by disaggregating denatured proteins through a poorly understood mechanism. Here, we present cryo-electron microscopy maps and domain fitting of Hsp104 hexamers, revealing an unusual arrangement of AAA+ modules with the prominent coiled-coil domain intercalated between the AAA+ domains. This packing results in a greatly expanded cavity, which is capped at either end by N- and C-terminal domains. The fitted structures as well as mutation of conserved coiled-coil arginines suggest that the coiled-coil domain plays a major role in the extraction of proteins from aggregates, providing conserved residues for key functions in ATP hydrolysis and potentially for substrate interaction. The large cavity could enable the uptake of polypeptide loops without a requirement for exposed N or C termini.

Original language	English
Pages (from-to)	1366-1377
Number of pages	12
Journal	Cell
Volume	131
Issue number	7
DOIs	https://doi.org/10.1016/j.cell.2007.10.047
State	Published - Dec 28 2007

Keywords

CELLBIO
PROTEINS

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10.1016/j.cell.2007.10.047

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title = "Atypical AAA+ Subunit Packing Creates an Expanded Cavity for Disaggregation by the Protein-Remodeling Factor Hsp104",

abstract = "Hsp104, a yeast protein-remodeling factor of the AAA+ (ATPases associated with various cellular activities) superfamily, and its homologs in bacteria and plants mediate cell recovery after severe stress by disaggregating denatured proteins through a poorly understood mechanism. Here, we present cryo-electron microscopy maps and domain fitting of Hsp104 hexamers, revealing an unusual arrangement of AAA+ modules with the prominent coiled-coil domain intercalated between the AAA+ domains. This packing results in a greatly expanded cavity, which is capped at either end by N- and C-terminal domains. The fitted structures as well as mutation of conserved coiled-coil arginines suggest that the coiled-coil domain plays a major role in the extraction of proteins from aggregates, providing conserved residues for key functions in ATP hydrolysis and potentially for substrate interaction. The large cavity could enable the uptake of polypeptide loops without a requirement for exposed N or C termini.",

keywords = "CELLBIO, PROTEINS",

author = "Petra Wendler and James Shorter and Celia Plisson and Cashikar, {Anil G.} and Susan Lindquist and Saibil, {Helen R.}",

note = "Funding Information: We thank Elena Orlova, Carolyn Moores, Maya Topf, David Wright and Doug Hattendorf for helpful discussions. We also wish to thank Luchun Wang for EM assistance; David Houldershaw and Richard Westlake for computing support; and Sukyeong Lee for providing us with the pPROEXHTb-Hsp104 ΔN plasmid. The American Heart Association (J.S.); National Institutes of Health (NIH) (S.L.), S.L. is an Investigator of the Howard Hughes Medical Institute; Wellcome Trust, the European Union Integrated Project 3D-Repertoire, and HFSP (H.S.) funded this work. ",

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AU - Wendler, Petra

AU - Shorter, James

AU - Plisson, Celia

AU - Cashikar, Anil G.

AU - Lindquist, Susan

AU - Saibil, Helen R.

N1 - Funding Information: We thank Elena Orlova, Carolyn Moores, Maya Topf, David Wright and Doug Hattendorf for helpful discussions. We also wish to thank Luchun Wang for EM assistance; David Houldershaw and Richard Westlake for computing support; and Sukyeong Lee for providing us with the pPROEXHTb-Hsp104 ΔN plasmid. The American Heart Association (J.S.); National Institutes of Health (NIH) (S.L.), S.L. is an Investigator of the Howard Hughes Medical Institute; Wellcome Trust, the European Union Integrated Project 3D-Repertoire, and HFSP (H.S.) funded this work.

PY - 2007/12/28

Y1 - 2007/12/28

N2 - Hsp104, a yeast protein-remodeling factor of the AAA+ (ATPases associated with various cellular activities) superfamily, and its homologs in bacteria and plants mediate cell recovery after severe stress by disaggregating denatured proteins through a poorly understood mechanism. Here, we present cryo-electron microscopy maps and domain fitting of Hsp104 hexamers, revealing an unusual arrangement of AAA+ modules with the prominent coiled-coil domain intercalated between the AAA+ domains. This packing results in a greatly expanded cavity, which is capped at either end by N- and C-terminal domains. The fitted structures as well as mutation of conserved coiled-coil arginines suggest that the coiled-coil domain plays a major role in the extraction of proteins from aggregates, providing conserved residues for key functions in ATP hydrolysis and potentially for substrate interaction. The large cavity could enable the uptake of polypeptide loops without a requirement for exposed N or C termini.

AB - Hsp104, a yeast protein-remodeling factor of the AAA+ (ATPases associated with various cellular activities) superfamily, and its homologs in bacteria and plants mediate cell recovery after severe stress by disaggregating denatured proteins through a poorly understood mechanism. Here, we present cryo-electron microscopy maps and domain fitting of Hsp104 hexamers, revealing an unusual arrangement of AAA+ modules with the prominent coiled-coil domain intercalated between the AAA+ domains. This packing results in a greatly expanded cavity, which is capped at either end by N- and C-terminal domains. The fitted structures as well as mutation of conserved coiled-coil arginines suggest that the coiled-coil domain plays a major role in the extraction of proteins from aggregates, providing conserved residues for key functions in ATP hydrolysis and potentially for substrate interaction. The large cavity could enable the uptake of polypeptide loops without a requirement for exposed N or C termini.

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Atypical AAA+ Subunit Packing Creates an Expanded Cavity for Disaggregation by the Protein-Remodeling Factor Hsp104

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