Hidden dynamics of proteasome autoregulation discovered by cryo-EM data-driven deep learning

The cellular functions are executed by macromolecular complexes in nonequilibrium dynamic processes, which exhibit a vast diversity of conformational states. Solving conformational continuum of important complexes at atomic level remains a key challenge in the methodology of computational biophysics...

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Bibliographic Details
Published inbioRxiv
Main Authors Wu, Zhaolong, Chen, Enbo, Zhang, Shuwen, Wei Li Wang, Ma, Yinping, Yuanchen Dong, Liu, Congcong, Chang-Cheng, Yin, Mao, Youdong
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 03.03.2022
Subjects
Adenosine triphosphatase
Binding sites
Electron microscopy
Free energy
Proteasome 26S
Proteasomes
Proteolysis
Ubiquitin
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Summary:The cellular functions are executed by macromolecular complexes in nonequilibrium dynamic processes, which exhibit a vast diversity of conformational states. Solving conformational continuum of important complexes at atomic level remains a key challenge in the methodology of computational biophysics. Here we introduce a deep-learning framework, named AlphaCryo4D, which enables atomic-level cryogenic electron microscopy reconstructions of nonequilibrium conformational continuum. AlphaCryo4D integrates 3D deep residual learning with manifold embedding of energy landscapes, which simultaneously improves 3D classification accuracy and reconstruction resolution via an energy-based particle-voting algorithm. Applications of this methodology to six experimental datasets demonstrated its generality in breaking resolution barrier of visualizing dynamic components of functional complexes, in choreographing continuous inter-subunit motions and in exploring their 'hidden' conformational space. Importantly, AlphaCryo4D identified 64 conformers of the substrate-bound human 26S proteasome and reconstituted single-nucleotide-exchange dynamics of proteasomal AAA-ATPase motor during translocation initiation, which together illuminates a grand hierarchical allostery for proteasome autoregulation. Competing Interest Statement The authors have declared no competing interest. Footnotes * This revision merged additional tests on experimental datasets from a standalone companion paper (https://www.biorxiv.org/content/10.1101/2021.08.09.455739v1).
DOI:10.1101/2020.12.22.423932