{"about":{"site":"https://codewithpapers.app","non_affiliation":"Code with Papers and Syntology are not affiliated with, endorsed by, or sponsored by Papers with Code, Meta, or the pwc-archive mirror.","licence":"CC BY-SA 4.0","licence_url":"https://creativecommons.org/licenses/by-sa/4.0/legalcode","attribution":"https://codewithpapers.app/attribution","modified":"archive material modified by Syntology; see the attribution page"},"url":"/paper/deep-manifold-learning-reveals-hidden","title":"Deep manifold learning reveals hidden dynamics of proteasome autoregulation","arxiv_id":"2012.12854","date":"2020-12-23","proceeding":null,"authors":["Zhaolong Wu","Shuwen Zhang","Wei Li Wang","Yinping Ma","Yuanchen Dong","Youdong Mao"],"abstract":"The 2.5-MDa 26S proteasome maintains proteostasis and regulates myriad cellular processes. How polyubiquitylated substrate interactions regulate proteasome activity is not understood. Here we introduce a deep manifold learning framework, named AlphaCryo4D, which enables atomic-level cryogenic electron microscopy (cryo-EM) reconstructions of nonequilibrium conformational continuum and reconstitutes hidden dynamics of proteasome autoregulation in the act of substrate degradation. AlphaCryo4D integrates 3D deep residual learning with manifold embedding of free-energy landscapes, which directs 3D clustering via an energy-based particle-voting algorithm. In blind assessments using simulated heterogeneous cryo-EM datasets, AlphaCryo4D achieved 3D classification accuracy three times that of conventional method and reconstructed continuous conformational changes of a 130-kDa protein at sub-3-angstrom resolution. By using AlphaCryo4D to analyze a single experimental cryo-EM dataset, we identified 64 conformers of the substrate-bound human 26S proteasome, revealing conformational entanglement of two regulatory particles in the doubly capped holoenzymes and their energetic differences with singly capped ones. Novel ubiquitin-binding sites are discovered on the RPN2, RPN10 and Alpha5 subunits to remodel polyubiquitin chains for deubiquitylation and recycle. Importantly, AlphaCryo4D choreographs single-nucleotide-exchange dynamics of proteasomal AAA-ATPase motor during translocation initiation, which upregulates proteolytic activity by allosterically promoting nucleophilic attack. Our systemic analysis illuminates a grand hierarchical allostery for proteasome autoregulation.","url_abs":"https://arxiv.org/abs/2012.12854v2","url_pdf":"https://arxiv.org/pdf/2012.12854v2.pdf","source":{"archive":"pwc-archive (Hugging Face), CC BY-SA 4.0","snapshot":"2025-07-28","licence_url":"https://creativecommons.org/licenses/by-sa/4.0/legalcode","row_kind":"abstracts"},"code_links":[{"paper_slug":"deep-manifold-learning-reveals-hidden","repo_url":"https://github.com/AlphaCryo4D/AlphaCryo4D","is_official":1,"mentioned_in_paper":0,"mentioned_in_github":0,"framework":"none","reach":null}],"tasks":[{"task_slug":"3d-classification","task_name":"3D Classification"},{"task_slug":"clustering","task_name":"Clustering"},{"task_slug":null,"task_name":"Cryogenic Electron Microscopy (cryo-EM)"}],"methods":[],"datasets_introduced":[],"methods_introduced":[],"results":[],"syntology":{"atlas_url":null,"mcp":null,"developers":"https://syntology.ai/developers"},"arxiv_metadata":null,"syntology_extracted_results":null}