title: Structural basis for dynamic regulation of the human 26S proteasome.
abstract: The proteasome is the major engine of protein degradation in all eukaryotic cells. At the heart of this machine is a heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitylated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides. Using cryoelectron microscopy, we determined a near-atomic-resolution structure of the 2.5-MDa human proteasome in its ground state, as well as subnanometer-resolution structures of the holoenzyme in three alternative conformational states. The substrate-unfolding AAA-ATPase channel is narrowed by 10 inward-facing pore loops arranged into two helices that run in parallel with each other, one hydrophobic in character and the other highly charged. The gate of the core particle was unexpectedly found closed in the ground state and open in only one of the alternative states. Coordinated, stepwise conformational changes of the regulatory particle couple ATP hydrolysis to substrate translocation and regulate gating of the core particle, leading to processive degradation.
authors: Center for Quantitative Biology, Peking University, Beijing 100871, China.|State Key Laboratory for Artificial Microstructures and Mesoscopic Physics, Institute of Condensed Matter Physics, School of Physics, Peking University, Beijing 100871, China.|Intel Parallel Computing Center for Structural Biology, Dana-Farber Cancer Institute, Boston, MA 02215.
authors: Shuobing
authors: S
authors: Chen
authors: State Key Laboratory for Artificial Microstructures and Mesoscopic Physics, Institute of Condensed Matter Physics, School of Physics, Peking University, Beijing 100871, China.
authors: Jiayi
authors: J
authors: Wu
authors: Department of Systems Biology, Harvard Medical School, Boston, MA 02115.
authors: Ying
authors: Y
authors: Lu
authors: Intel Parallel Computing Center for Structural Biology, Dana-Farber Cancer Institute, Boston, MA 02215.
authors: Yong-Bei
authors: YB
authors: Ma
authors: Department of Cell Biology, Harvard Medical School, Boston, MA 02115.
authors: Byung-Hoon
authors: BH
authors: Lee
authors: Department of Molecular and Cellular Biology, Graduate School of Arts and Sciences, Harvard University, Cambridge, MA 02138.
authors: Zhou
authors: Z
authors: Yu
authors: Center for Quantitative Biology, Peking University, Beijing 100871, China.|State Key Laboratory for Artificial Microstructures and Mesoscopic Physics, Institute of Condensed Matter Physics, School of Physics, Peking University, Beijing 100871, China.|Peking-Tsinghua Joint Center for Life Sciences, Peking University, Beijing 100871, China.
authors: Qi
authors: Q
authors: Ouyang
authors: Department of Cell Biology, Harvard Medical School, Boston, MA 02115.
authors: Daniel J
authors: DJ
authors: Finley
authors: Department of Systems Biology, Harvard Medical School, Boston, MA 02115; marc@hms.harvard.edu youdong_mao@dfci.harvard.edu.
authors: Marc W
authors: MW
authors: Kirschner
authors: Center for Quantitative Biology, Peking University, Beijing 100871, China; marc@hms.harvard.edu youdong_mao@dfci.harvard.edu.|State Key Laboratory for Artificial Microstructures and Mesoscopic Physics, Institute of Condensed Matter Physics, School of Physics, Peking University, Beijing 100871, China.|Intel Parallel Computing Center for Structural Biology, Dana-Farber Cancer Institute, Boston, MA 02215.|Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115.|Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115.
authors: Youdong
authors: Y
authors: Mao
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000378:metabolism; D020285:Cryoelectron Microscopy; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure*; D011487:Protein Conformation
chemical_list: D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D000251:Adenosine Triphosphatases
keywords: AAA-ATPase; cyroelectron microscopy; ubiquitin-proteasome system