Physiological levels of ATP negatively regulate proteasome function

Huang, Hongbiao; Zhang, Xiaoyan; Li, Shujue; Liu, Ningning; Lian, Wen; McDowell, Emily J.; Zhou, Ping; Zhao, Canguo; Guo, Haiping; Zhang, Change; Yang, Changshan; Wen, Guangmei; Dong, Xin; Lu, Li; Ma, Ning‐Fang; Dong, Wei; Dou, Q. Ping; Wang, Xuejun; Liu, Jinbao

doi:10.1038/cr.2010.123

Cited by 130 publications

(117 citation statements)

References 39 publications

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“…Table II shows the three-state parameterization of kinesin from Clancy et al [16]. Typical physiological ATP concentrations in the low millimolars [48] motivate the approximation [ATP]∼1mM, giving k + 12 , and hence ω 12 ≃ 4. The second and third transitions are considered 'irreversible,' so we assume that the remaining dissipation budget (from the 20 k B T free energy provided by ATP hydrolysis) is evenly split to these two transitions, so that ω 23 = ω 31 = 8, providing values for k − 23 and k − 31 .…”

Section: Appendix B: Additional Model Detailsmentioning

confidence: 99%

Allocating dissipation across a molecular machine cycle to maximize flux

Brown

Sivak

2017

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

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Biomolecular machines consume free energy to break symmetry and make directed progress. Nonequilibrium ATP concentrations are the typical free energy source, with one cycle of a molecular machine consuming a certain number of ATP, providing a fixed free energy budget. Since evolution is expected to favor rapid-turnover machines that operate efficiently, we investigate how this free energy budget can be allocated to maximize flux. Unconstrained optimization eliminates intermediate metastable states, indicating that flux is enhanced in molecular machines with fewer states. When maintaining a set number of states, we show that-in contrast to previous findings-the fluxmaximizing allocation of dissipation is not even. This result is consistent with the coexistence of both 'irreversible' and reversible transitions in molecular machine models that successfully describe experimental data, which suggests that in evolved machines different transitions differ significantly in their dissipation.

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Section: Appendix B: Additional Model Detailsmentioning

confidence: 99%

Allocating dissipation across a molecular machine cycle to maximize flux

Brown

Sivak

2017

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

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“…Of the top 10 compounds, only compound 1 was more than 10-fold less potent in blocking ODD-Luc degradation compared with Ub G76V -GFP degradation. As a further test of the selectivity of this compound we evaluated its ability to inhibit AAA ATPase activity of purified N-ethylmaleimidesensitive factor (NSF) (25) and the ATP-dependent chymotryptic activity of 26S proteasome (26). Compound 1 [which we have renamed as N 2 ,N 4 -dibenzylquinazoline-2,4-diamine (DBeQ)] was at least 50-fold less potent toward these enzymes (Fig.…”

Section: Resultsmentioning

confidence: 99%

Reversible inhibitor of p97, DBeQ, impairs both ubiquitin-dependent and autophagic protein clearance pathways

Chou

Brown²,

Minond³

et al. 2011

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

294

350

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A specific small-molecule inhibitor of p97 would provide an important tool to investigate diverse functions of this essential ATPase associated with diverse cellular activities (AAA) ATPase and to evaluate its potential to be a therapeutic target in human disease. We carried out a high-throughput screen to identify inhibitors of p97 ATPase activity. Dual-reporter cell lines that simultaneously express p97-dependent and p97-independent proteasome substrates were used to stratify inhibitors that emerged from the screen. N 2 ,N 4 -dibenzylquinazoline-2,4-diamine (DBeQ) was identified as a selective, potent, reversible, and ATP-competitive p97 inhibitor. DBeQ blocks multiple processes that have been shown by RNAi to depend on p97, including degradation of ubiquitin fusion degradation and endoplasmic reticulum-associated degradation pathway reporters, as well as autophagosome maturation. DBeQ also potently inhibits cancer cell growth and is more rapid than a proteasome inhibitor at mobilizing the executioner caspases-3 and -7. Our results provide a rationale for targeting p97 in cancer therapy.apoptosis | autophagy | unfolded protein response T he AAA (ATPase associated with diverse cellular activities) ATPase p97 is conserved across all eukaryotes and is essential for life in budding yeast (1) and mice (2). p97 was first linked to the ubiquitin-proteasome system (UPS) through its role in the turnover of ubiquitin−β-galactosidase fusion proteins via the "ubiquitin fusion degradation" (UFD) pathway (3). Since then, p97 has been shown to play a critical role in the degradation of misfolded membrane and secretory proteins (4) and has also been linked to a broad array of cellular processes, including Golgi membrane reassembly (5), membrane transport (6), regulation of myofibril assembly (7), cell division (8), formation of protein aggregates (9), and autophagosome maturation (10, 11). The broad range of cellular functions for p97 is thought to derive from its ability to unfold proteins or disassemble protein complexes, but the detailed mechanism of how p97 works and is linked to specific cellular processes remains largely unknown.The structure of p97 comprises three domains: an N-terminal domain that recruits adaptors/substrate specificity factors, followed by two ATPase domains, D1 and D2 (12, 13). p97 monomers assemble to form a homohexamer that is thought to provide a platform for transduction of chemical activity into mechanical force that is applied to substrate proteins. The D1 domain mediates hexamerization (14) and has very low ATPase activity (15). Most of the ATPase activity is contributed by the D2 domain, which is thought to underlie p97's function as a mechanochemical transducer (16).The mechanochemical activity of p97 is linked to substrate proteins by an array of 13 UBX (ubiquitin regulatory X) domain adapters that bind the N-terminal domain of p97 (17), as well as the non-UBX domain adaptors Ufd1 and Npl4 (18). The functions and mechanisms of action of these different p97-adaptor complexes remain poorly u...

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“…An intriguing hypothesis posits that physiological ATP levels may negatively regulate proteasome function under normal circumstances. 70 Powell et al 62 reported that the optimal ATP concentration for in vitro proteasome activity is <100 μmol/L and that higher ATP concentrations inhibit proteasome peptidase activities. On the other hand, it is well known that the physiological intracellular ATP concentration in many cell types is greatly higher (by a factor >10) than such values.…”

Section: Ischemia-reperfusion Injurymentioning

confidence: 99%

Role of the Ubiquitin Proteasome System in the Heart

Pagan

Seto

Pagano

et al. 2013

Circulation Research

121

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Abstract:Proper protein turnover is required for cardiac homeostasis and, accordingly, impaired proteasomal function appears to contribute to heart disease. Specific proteasomal degradation mechanisms underlying cardiovascular biology and disease have been identified, and such cellular pathways have been proposed to be targets of clinical relevance. This review summarizes the latest literature regarding the specific E3 ligases involved in heart biology, and the general ways that the proteasome regulates protein quality control in heart disease. The potential for therapeutic intervention in Ubiquitin Proteasome System function in heart disease is discussed. (Circ Res. 2013;112:1046-1058.)

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Physiological levels of ATP negatively regulate proteasome function

Cited by 130 publications

References 39 publications

Allocating dissipation across a molecular machine cycle to maximize flux

Allocating dissipation across a molecular machine cycle to maximize flux

Reversible inhibitor of p97, DBeQ, impairs both ubiquitin-dependent and autophagic protein clearance pathways

Role of the Ubiquitin Proteasome System in the Heart

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