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Long-range allosteric regulation of the human 26S proteasome by 20S proteasome-targeting cancer drugs.

Haselbach D, Schrader J, Lambrecht F, Henneberg F, Chari A, Stark H
Nat Commun 8 15578 (2017)
Cited: 35 times
EuropePMC logo PMID: 28541292

Abstract

The proteasome holoenzyme is the major non-lysosomal protease; its proteolytic activity is essential for cellular homeostasis. Thus, it is an attractive target for the development of chemotherapeutics. While the structural basis of core particle (CP) inhibitors is largely understood, their structural impact on the proteasome holoenzyme remains entirely elusive. Here, we determined the structure of the 26S proteasome with and without the inhibitor Oprozomib. Drug binding modifies the energy landscape of conformational motion in the proteasome regulatory particle (RP). Structurally, the energy barrier created by Oprozomib triggers a long-range allosteric regulation, resulting in the stabilization of a non-productive state. Thereby, the chemical drug-binding signal is converted, propagated and amplified into structural changes over a distance of more than 150 Å from the proteolytic site to the ubiquitin receptor Rpn10. The direct visualization of changes in conformational dynamics upon drug binding allows new ways to screen and develop future allosteric proteasome inhibitors.

Reviews - 5m32 mentioned but not cited (1)

  1. A Practical Review of Proteasome Pharmacology. Thibaudeau TA, Smith DM. Pharmacol Rev 71 170-197 (2019)

Articles - 5m32 mentioned but not cited (2)

  1. Long-range allosteric regulation of the human 26S proteasome by 20S proteasome-targeting cancer drugs. Haselbach D, Schrader J, Lambrecht F, Henneberg F, Chari A, Stark H. Nat Commun 8 15578 (2017)
  2. FTIP: an accurate and efficient method for global protein surface comparison. Zhang Y, Sui X, Stagg S, Zhang J. Bioinformatics 36 3056-3063 (2020)


Reviews citing this publication (14)

  1. Structural Insights into Nuclear pre-mRNA Splicing in Higher Eukaryotes. Kastner B, Will CL, Stark H, Lührmann R. Cold Spring Harb Perspect Biol 11 a032417 (2019)
  2. Structure and Function of the 26S Proteasome. Bard JAM, Goodall EA, Greene ER, Jonsson E, Dong KC, Martin A. Annu. Rev. Biochem. 87 697-724 (2018)
  3. Structure, Dynamics and Function of the 26S Proteasome. Mao Y. Subcell Biochem 96 1-151 (2021)
  4. Fatty Acid Synthase: Structure, Function, and Regulation. Günenc AN, Graf B, Stark H, Chari A. Subcell Biochem 99 1-33 (2022)
  5. Understanding the 26S proteasome molecular machine from a structural and conformational dynamics perspective. Greene ER, Dong KC, Martin A. Curr Opin Struct Biol 61 33-41 (2020)
  6. Frozen in time: analyzing molecular dynamics with time-resolved cryo-EM. Amann SJ, Keihsler D, Bodrug T, Brown NG, Haselbach D. Structure 31 4-19 (2023)
  7. AAA+ ATPases in Protein Degradation: Structures, Functions and Mechanisms. Zhang S, Mao Y. Biomolecules 10 (2020)
  8. Allostery Modulates Interactions between Proteasome Core Particles and Regulatory Particles. Coffino P, Cheng Y. Biomolecules 12 764 (2022)
  9. Chromatography-Free Purification Strategies for Large Biological Macromolecular Complexes Involving Fractionated PEG Precipitation and Density Gradients. Henneberg F, Chari A. Life (Basel) 11 1289 (2021)
  10. Cryo-EM Analyses Permit Visualization of Structural Polymorphism of Biological Macromolecules. Chang WH, Huang SH, Lin HH, Chung SC, Tu IP. Front Bioinform 1 788308 (2021)
  11. Hands on Methods for High Resolution Cryo-Electron Microscopy Structures of Heterogeneous Macromolecular Complexes. Serna M. Front Mol Biosci 6 33 (2019)
  12. Large-Scale Conformational Changes and Protein Function: Breaking the in silico Barrier. Orellana L. Front Mol Biosci 6 117 (2019)
  13. Structural Analysis of Protein Complexes by Cryo-Electron Microscopy. Ignatiou A, Macé K, Redzej A, Costa TRD, Waksman G, Orlova EV. Methods Mol Biol 2715 431-470 (2024)
  14. Uncovering structural ensembles from single-particle cryo-EM data using cryoDRGN. Kinman LF, Powell BM, Zhong ED, Berger B, Davis JH. Nat Protoc 18 319-339 (2023)

Articles citing this publication (18)

  1. Characterisation of molecular motions in cryo-EM single-particle data by multi-body refinement in RELION. Nakane T, Kimanius D, Lindahl E, Scheres SH. Elife 7 (2018)
  2. The impact of AlphaFold2 on experimental structure solution. Edich M, Briggs DC, Kippes O, Gao Y, Thorn A. Faraday Discuss 240 184-195 (2022)
  3. Quantifying the heterogeneity of macromolecular machines by mass photometry. Sonn-Segev A, Belacic K, Bodrug T, Young G, VanderLinden RT, Schulman BA, Schimpf J, Friedrich T, Dip PV, Schwartz TU, Bauer B, Peters JM, Struwe WB, Benesch JLP, Brown NG, Haselbach D, Kukura P. Nat Commun 11 1772 (2020)
  4. Structure of RyR1 in native membranes. Chen W, Kudryashev M. EMBO Rep 21 e49891 (2020)
  5. GID E3 ligase supramolecular chelate assembly configures multipronged ubiquitin targeting of an oligomeric metabolic enzyme. Sherpa D, Chrustowicz J, Qiao S, Langlois CR, Hehl LA, Gottemukkala KV, Hansen FM, Karayel O, von Gronau S, Prabu JR, Mann M, Alpi AF, Schulman BA. Mol Cell 81 2445-2459.e13 (2021)
  6. The allosteric modulation of complement C5 by knob domain peptides. Macpherson A, Laabei M, Ahdash Z, Graewert MA, Birtley JR, Schulze ME, Crennell S, Robinson SA, Holmes B, Oleinikovas V, Nilsson PH, Snowden J, Ellis V, Mollnes TE, Deane CM, Svergun D, Lawson AD, van den Elsen JM. Elife 10 e63586 (2021)
  7. A nanobody-based fluorescent reporter reveals human α-synuclein in the cell cytosol. Gerdes C, Waal N, Offner T, Fornasiero EF, Wender N, Verbarg H, Manzini I, Trenkwalder C, Mollenhauer B, Strohäker T, Zweckstetter M, Becker S, Rizzoli SO, Basmanav FB, Opazo F. Nat Commun 11 2729 (2020)
  8. Characterization of Fully Recombinant Human 20S and 20S-PA200 Proteasome Complexes. Toste Rêgo A, da Fonseca PCA. Mol. Cell 76 138-147.e5 (2019)
  9. Cryo-EM structure of the plant 26S proteasome. Kandolf S, Grishkovskaya I, Belačić K, Bolhuis DL, Amann S, Foster B, Imre R, Mechtler K, Schleiffer A, Tagare HD, Zhong ED, Meinhart A, Brown NG, Haselbach D. Plant Commun 3 100310 (2022)
  10. Engineered disulfide crosslinking to measure conformational changes in the 26S proteasome. Reed RG, Tomko RJ. Methods Enzymol 619 145-159 (2019)
  11. Allosteric coupling between α-rings of the 20S proteasome. Yu Z, Yu Y, Wang F, Myasnikov AG, Coffino P, Cheng Y. Nat Commun 11 4580 (2020)
  12. Allosteric regulation of the 20S proteasome by the Catalytic Core Regulators (CCRs) family. Deshmukh FK, Ben-Nissan G, Olshina MA, Füzesi-Levi MG, Polkinghorn C, Arkind G, Leushkin Y, Fainer I, Fleishman SJ, Tawfik D, Sharon M. Nat Commun 14 3126 (2023)
  13. PSMC2 is Up-regulated in Pancreatic Cancer and Promotes Cancer Cell Proliferation and Inhibits Apoptosis. Qin J, Wang W, An F, Huang W, Ding J. J Cancer 10 4939-4946 (2019)
  14. PSMC2 is overexpressed in glioma and promotes proliferation and anti-apoptosis of glioma cells. Zheng X, Wang Y, Wang D, Wan J, Qin X, Mu Z, Hu N. World J Surg Oncol 20 84 (2022)
  15. Prognostic and Genomic Analysis of Proteasome 20S Subunit Alpha (PSMA) Family Members in Breast Cancer. Chiao CC, Liu YH, Phan NN, An Ton NT, Ta HDK, Anuraga G, Minh Xuan DT, Fitriani F, Putri Hermanto EM, Athoillah M, Andriani V, Ajiningrum PS, Wu YF, Lee KH, Chuang JY, Wang CY, Kao TJ. Diagnostics (Basel) 11 2220 (2021)
  16. Tagging the proteasome active site β5 causes tag specific phenotypes in yeast. Waite KA, Burris A, Roelofs J. Sci Rep 10 18133 (2020)
  17. USP14-regulated allostery of the human proteasome by time-resolved cryo-EM. Zhang S, Zou S, Yin D, Zhao L, Finley D, Wu Z, Mao Y. Nature 605 567-574 (2022)
  18. Visualizing Conformational Space of Functional Biomolecular Complexes by Deep Manifold Learning. Wu Z, Chen E, Zhang S, Ma Y, Mao Y. Int J Mol Sci 23 8872 (2022)


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