The Hsp104 N-Terminal Domain Enables Disaggregase Plasticity and Potentiation

Elizabeth A. Sweeny, Meredith E. Jackrel, Michelle S. Go, Matthew A. Sochor, Beatrice M. Razzo, Morgan E. DeSantis, Kushol Gupta, James Shorter

Research output: Contribution to journalArticlepeer-review

75 Scopus citations


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 (Hsp104δN) dissolves disordered aggregates but cannot dissolve prions or be potentiated by activating mutations. We define how Hsp104δN 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 Hsp104δN. We establish that the Hsp104 NTD enables cooperative substrate translocation, which is critical for prion dissolution and potentiated disaggregase activity.

Original languageEnglish
Pages (from-to)836-849
Number of pages14
JournalMolecular cell
Issue number5
StatePublished - Mar 5 2015


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