Hsp104 and Potentiated Variants Can Operate as Distinct Nonprocessive Translocases

Clarissa L. Durie, Jia Bei Lin, Nathaniel W. Scull, Korrie L. Mack, Meredith E. Jackrel, Elizabeth A. Sweeny, Laura M. Castellano, James Shorter, Aaron L. Lucius

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Heat shock protein (Hsp) 104 is a hexameric ATPases associated with diverse cellular activities motor protein that enables cells to survive extreme stress. Hsp104 couples the energy of ATP binding and hydrolysis to solubilize proteins trapped in aggregated structures. The mechanism by which Hsp104 disaggregates proteins is not completely understood but may require Hsp104 to partially or completely translocate polypeptides across its central channel. Here, we apply transient state, single turnover kinetics to investigate the ATP-dependent translocation of soluble polypeptides by Hsp104 and Hsp104A503S, a potentiated variant developed to resolve misfolded conformers implicated in neurodegenerative disease. We establish that Hsp104 and Hsp104A503S can operate as nonprocessive translocases for soluble substrates, indicating a “partial threading” model of translocation. Remarkably, Hsp104A503S exhibits altered coupling of ATP binding to translocation and decelerated dissociation from polypeptide substrate compared to Hsp104. This altered coupling and prolonged substrate interaction likely increases entropic pulling forces, thereby enabling more effective aggregate dissolution by Hsp104A503S.

Original languageEnglish
Pages (from-to)1856-1872
Number of pages17
JournalBiophysical Journal
Volume116
Issue number10
DOIs
StatePublished - May 21 2019

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