Conformational switching in the coiled-coil domains of a proteasomal ATPase regulates substrate processing

Aaron Snoberger, Evan J. Brettrager and David M. Smith ()
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Aaron Snoberger: West Virginia University School of Medicine
Evan J. Brettrager: West Virginia University School of Medicine
David M. Smith: West Virginia University School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract Protein degradation in all domains of life requires ATPases that unfold and inject proteins into compartmentalized proteolytic chambers. Proteasomal ATPases in eukaryotes and archaea contain poorly understood N-terminally conserved coiled-coil domains. In this study, we engineer disulfide crosslinks in the coiled-coils of the archaeal proteasomal ATPase (PAN) and report that its three identical coiled-coil domains can adopt three different conformations: (1) in-register and zipped, (2) in-register and partially unzipped, and (3) out-of-register. This conformational heterogeneity conflicts with PAN’s symmetrical OB-coiled-coil crystal structure but resembles the conformational heterogeneity of the 26S proteasomal ATPases’ coiled-coils. Furthermore, we find that one coiled-coil can be conformationally constrained even while unfolding substrates, and conformational changes in two of the coiled-coils regulate PAN switching between resting and active states. This switching functionally mimics similar states proposed for the 26S proteasome from cryo-EM. These findings thus build a mechanistic framework to understand regulation of proteasome activity.

Date: 2018
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DOI: 10.1038/s41467-018-04731-6

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