Tunable microsecond dynamics of an allosteric switch regulate the activity of a AAA+ disaggregation machine

Hisham Mazal, Marija Iljina, Yoav Barak, Nadav Elad, Rina Rosenzweig, Pierre Goloubinoff, Inbal Riven and Gilad Haran ()
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Hisham Mazal: Weizmann Institute of Science
Marija Iljina: Weizmann Institute of Science
Yoav Barak: Weizmann Institute of Science
Nadav Elad: Weizmann Institute of Science
Rina Rosenzweig: Weizmann Institute of Science
Pierre Goloubinoff: University of Lausanne
Inbal Riven: Weizmann Institute of Science
Gilad Haran: Weizmann Institute of Science

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract Large protein machines are tightly regulated through allosteric communication channels. Here we demonstrate the involvement of ultrafast conformational dynamics in allosteric regulation of ClpB, a hexameric AAA+ machine that rescues aggregated proteins. Each subunit of ClpB contains a unique coiled-coil structure, the middle domain (M domain), proposed as a control element that binds the co-chaperone DnaK. Using single-molecule FRET spectroscopy, we probe the M domain during the chaperone cycle and find it to jump on the microsecond time scale between two states, whose structures are determined. The M-domain jumps are much faster than the overall activity of ClpB, making it an effectively continuous, tunable switch. Indeed, a series of allosteric interactions are found to modulate the dynamics, including binding of nucleotides, DnaK and protein substrates. This mode of dynamic control enables fast cellular adaptation and may be a general mechanism for the regulation of cellular machineries.

Date: 2019
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DOI: 10.1038/s41467-019-09474-6

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