期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 6, 页码 1305-1310出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1621129114
关键词
26S proteasome; cryo-electron microscopy; AAA(+) ATPase; integrative modeling; single-particle analysis
资金
- German Science Foundation [Excellence Cluster Center for Integrated Protein Science Munich (CIPSM)] [SFB-1035/Project A01]
- National Science Foundation (NSF) [PHY1430124]
- NIH [9P41GM104601]
- NSF [MCA93S028, OCI-0725070, ACI-1238993]
- Marie Curie Career Integration Grant [PCIG14-GA-2013-631577]
- Feodor Lynen von Humboldt Postdoctoral Fellowship
- Direct For Computer & Info Scie & Enginr
- Office of Advanced Cyberinfrastructure (OAC) [1440026] Funding Source: National Science Foundation
In eukaryotic cells, the ubiquitin-proteasome system (UPS) is responsible for the regulated degradation of intracellular proteins. The 26S holocomplex comprises the core particle (CP), where proteolysis takes place, and one or two regulatory particles (RPs). The base of the RP is formed by a heterohexameric AAA(+) ATPase module, which unfolds and translocates substrates into the CP. Applying single-particle cryo-electron microscopy (cryo-EM) and image classification to samples in the presence of different nucleotides and nucleotide analogs, we were able to observe four distinct conformational states (s1 to s4). The resolution of the four conformers allowed for the construction of atomic models of the AAA(+) ATPase module as it progresses through the functional cycle. In a hitherto unobserved state (s4), the gate controlling access to the CP is open. The structures described in this study allow us to put forward a model for the 26S functional cycle driven by ATP hydrolysis.
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