The proteasome under the microscope: the regulatory particle in focus

Lander, Gabriel C.; Martin, Andreas; Nogales, Eva

doi:10.1016/j.sbi.2013.02.004

Cited by 37 publications

(31 citation statements)

References 42 publications

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“…The different RP architecture in ref. 22 is likely an artifact of an overestimation of the resolution, which resulted in misinterpretation of the map, as previously suggested (26).…”

Section: Resultsmentioning

confidence: 75%

Structure of the human 26S proteasome at a resolution of 3.9 Å

Schweitzer

Aufderheide

Rudack

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

187

220

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Protein degradation in eukaryotic cells is performed by the UbiquitinProteasome System (UPS). The 26S proteasome holocomplex consists of a core particle (CP) that proteolytically degrades polyubiquitylated proteins, and a regulatory particle (RP) containing the AAA-ATPase module. This module controls access to the proteolytic chamber inside the CP and is surrounded by non-ATPase subunits (Rpns) that recognize substrates and deubiquitylate them before unfolding and degradation. The architecture of the 26S holocomplex is highly conserved between yeast and humans. The structure of the human 26S holocomplex described here reveals previously unidentified features of the AAA-ATPase heterohexamer. One subunit, Rpt6, has ADP bound, whereas the other five have ATP in their binding pockets. Rpt6 is structurally distinct from the other five Rpt subunits, most notably in its pore loop region. For Rpns, the map reveals two main, previously undetected, features: the C terminus of Rpn3 protrudes into the mouth of the ATPase ring; and Rpn1 and Rpn2, the largest proteasome subunits, are linked by an extended connection. The structural features of the 26S proteasome observed in this study are likely to be important for coordinating the proteasomal subunits during substrate processing.proteostasis | cryo-electron microscopy | AAA-ATPase | integrative modeling T he 26S proteasome is an ATP-dependent multisubunit protease degrading polyubiquitylated proteins (1, 2). It operates at the executive end of the Ubiquitin-Proteasome System (UPS) and has a key role in cellular proteostasis. The 26S proteasome selectively removes misfolded proteins or proteins no longer needed and it is critically involved in numerous cellular processes such as protein quality control, regulation of metabolism, cell cycle control, or antigen presentation. Malfunctions of the UPS are associated with various pathologies, including neurodegenerative diseases and cancer. Therefore, the proteasome is an important pharmaceutical target, and a high-resolution structure is a prerequisite for structure-based drug design (3).The 26S proteasome comprises the 20S cylindrical core particle (CP), where proteolysis takes place, and 19S regulatory particles (RPs). In cellular environments, 26S holocomplexes with either one or two RPs bound to the ends of the cylindershaped CP coexist (4). The role of the RPs is to recruit ubiquitylated substrates, to cleave off their polyubiquitin tags, and to unfold and translocate them into the CP for degradation into short peptides. Whereas X-ray crystallography has revealed the atomic structures first of archaeal 20S proteasome (5) and subsequently of the yeast (6) and mammalian proteasome (7), only lower-resolution structures were available for the 26S holocomplex. Given the compositional and conformational heterogeneity of the RP, single-particle cryo-electron microscopy (cryo-EM) has been the most successful approach to determining the structure of the 26S holocomplex (8). At this point, the most detailed insights have been obtained ...

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“…The different RP architecture in ref. 22 is likely an artifact of an overestimation of the resolution, which resulted in misinterpretation of the map, as previously suggested (26).…”

Section: Resultsmentioning

confidence: 75%

Structure of the human 26S proteasome at a resolution of 3.9 Å

Schweitzer

Aufderheide

Rudack

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

187

220

View full text Add to dashboard Cite

show abstract

“…The proteasome consists of two major assemblies, the core particle and the regulatory particle. The core particle houses the proteolytic active sites within a central cylindrical chamber, whereas the regulatory particle, which sits at either end of the core particle, orchestrates the recognition, unfolding, deubiquitination, and insertion of substrates into the core particle (21).…”

Section: Resultsmentioning

confidence: 99%

Proteomic Analysis Identifies Ribosome Reduction as an Effective Proteotoxic Stress Response

Guerra-Moreno

Isasa

Bhanu

et al. 2015

Journal of Biological Chemistry

119

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Background: Misfolded proteins are a ubiquitous and clinically relevant threat to cells. Results: Arsenite stress in yeast leads to increased protein degradation and reduced protein production. Conclusion: Reduction in ribosome abundance is a novel, rapid, effective, and reversible stress response against misfolded proteins. Significance: These results provide the basis for further characterization of a potentially important stress response pathway.

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“…The initial set of reports presented proteasome structures that were prepared in the presence of saturating ATP levels 65–68 whereas the more recent papers show proteasome in the presence of substrate 69 or with a slowly hydrolysable ATP analogue (ATPγS) 70 . These studies combined high-resolution EM structures of the particle with crystal structures and homology models of isolated subunits, and a wealth of biochemical, proteomic and genetic analyses to determine the structure of the 26S proteasome 71, 72 . Together, the approaches place all of the known stoichiometric subunits within the particle and in many cases orient their crystal structures well enough to interpret information at atomic resolution in meaningful ways 65–68, 73 .…”

Section: A Complex Of Two Halvesmentioning

confidence: 99%

Regulated protein turnover: snapshots of the proteasome in action

Bhattacharyya

Mim

et al. 2014

Nat Rev Mol Cell Biol

225

220

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The ubiquitin-proteasome system (UPS) is the main ATP-dependent protein degradation pathway in the cytosol and nucleus of eukaryotic cells. At its centre is the 26S proteasome, which degrades regulatory proteins and mis-folded or damaged proteins. In a major breakthrough, several groups have determined high-resolution structures of the entire 26S proteasome particle in different nucleotide conditions and with and without substrate using cryo-electron microscopy combined with other techniques. These structures bring some surprising insights into the functional mechanism of the proteasome and will provide invaluable guidance for genetic and biochemical studies of this key regulatory system.

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The proteasome under the microscope: the regulatory particle in focus

Cited by 37 publications

References 42 publications

Structure of the human 26S proteasome at a resolution of 3.9 Å

Structure of the human 26S proteasome at a resolution of 3.9 Å

Proteomic Analysis Identifies Ribosome Reduction as an Effective Proteotoxic Stress Response

Regulated protein turnover: snapshots of the proteasome in action

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