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The Hsp104 N-terminal domain enables disaggregase plasticity and potentiation. Mol Cell 2015 Mar 05;57(5):836-849

Date

01/27/2015

Pubmed ID

25620563

Pubmed Central ID

PMC4623595

DOI

10.1016/j.molcel.2014.12.021

Scopus ID

2-s2.0-84924037150 (requires institutional sign-in at Scopus site)   79 Citations

Abstract

The structural basis by which Hsp104 dissolves disordered aggregates and prions is unknown. A single subunit within the Hsp104 hexamer can solubilize disordered aggregates, whereas prion dissolution requires collaboration by multiple Hsp104 subunits. Here, we establish that the poorly understood Hsp104 N-terminal domain (NTD) enables this operational plasticity. Hsp104 lacking the NTD (Hsp104(ΔN)) dissolves disordered aggregates but cannot dissolve prions or be potentiated by activating mutations. We define how Hsp104(ΔN) invariably stimulates Sup35 prionogenesis by fragmenting prions without solubilizing Sup35, whereas Hsp104 couples Sup35 prion fragmentation and dissolution. Volumetric reconstruction of Hsp104 hexamers in ATPγS, ADP-AlFx (hydrolysis transition state mimic), and ADP via small-angle X-ray scattering revealed a peristaltic pumping motion upon ATP hydrolysis, which drives directional substrate translocation through the central Hsp104 channel and is profoundly altered in Hsp104(ΔN). We establish that the Hsp104 NTD enables cooperative substrate translocation, which is critical for prion dissolution and potentiated disaggregase activity.

Author List

Sweeny EA, Jackrel ME, Go MS, Sochor MA, Razzo BM, DeSantis ME, Gupta K, Shorter J

Authors

Matthew A. Sochor Postdoctoral Researcher in the Biochemistry department at Medical College of Wisconsin
Elizabeth Sweeny PhD Assistant Professor in the Biochemistry department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adenosine Triphosphate
Adenylyl Imidodiphosphate
Heat-Shock Proteins
Microscopy, Electron
Microscopy, Fluorescence
Models, Molecular
Mutation
Peptide Termination Factors
Protein Binding
Protein Multimerization
Protein Structure, Tertiary
Saccharomyces cerevisiae
Saccharomyces cerevisiae Proteins
Scattering, Small Angle
X-Ray Diffraction