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Structure and energetics of pairwise interactions between proteasome subunits RPN2, RPN13, and ubiquitin clarify a substrate recruitment mechanism.

VanderLinden RT, Hemmis CW, Yao T, Robinson H, Hill CP
J Biol Chem 292 9493-9504 (2017)
Cited: 30 times
EuropePMC logo PMID: 28442575

Abstract

The 26S proteasome is a large cellular assembly that mediates the selective degradation of proteins in the nucleus and cytosol and is an established target for anticancer therapeutics. Protein substrates are typically targeted to the proteasome through modification with a polyubiquitin chain, which can be recognized by several proteasome-associated ubiquitin receptors. One of these receptors, RPN13/ADRM1, is recruited to the proteasome through direct interaction with the large scaffolding protein RPN2 within the 19S regulatory particle. To better understand the interactions between RPN13, RPN2, and ubiquitin, we used human proteins to map the RPN13-binding epitope to the C-terminal 14 residues of RPN2, which, like ubiquitin, binds the N-terminal pleckstrin-like receptor of ubiquitin (PRU) domain of RPN13. We also report the crystal structures of the RPN13 PRU domain in complex with peptides corresponding to the RPN2 C terminus and ubiquitin. Through mutational analysis, we validated the RPN2-binding interface revealed by our structures and quantified binding interactions with surface plasmon resonance and fluorescence polarization. In contrast to a previous report, we find that RPN13 binds ubiquitin with an affinity similar to that of other proteasome-associated ubiquitin receptors and that RPN2, ubiquitin, and the deubiquitylase UCH37 bind to RPN13 with independent energetics. These findings provide a detailed characterization of interactions that are important for proteasome function, indicate ubiquitin affinities that are consistent with the role of RPN13 as a proteasomal ubiquitin receptor, and have major implications for the development of novel anticancer therapeutics.

Reviews - 5v1z mentioned but not cited (1)

  1. 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)

Articles - 5v1z mentioned but not cited (1)

  1. Structure and energetics of pairwise interactions between proteasome subunits RPN2, RPN13, and ubiquitin clarify a substrate recruitment mechanism. VanderLinden RT, Hemmis CW, Yao T, Robinson H, Hill CP. J Biol Chem 292 9493-9504 (2017)


Reviews citing this publication (6)

  1. Proteasome interaction with ubiquitinated substrates: from mechanisms to therapies. Chen X, Htet ZM, López-Alfonzo E, Martin A, Walters KJ. FEBS J 288 5231-5251 (2021)
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  5. Small-Molecule Inhibitors of the Proteasome's Regulatory Particle. Muli CS, Tian W, Trader DJ. Chembiochem 20 1739-1753 (2019)
  6. To Kill or to Be Killed: How Does the Battle between the UPS and Autophagy Maintain the Intracellular Homeostasis in Eukaryotes? Yu P, Hua Z. Int J Mol Sci 24 2221 (2023)

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  2. Structure of Human NatA and Its Regulation by the Huntingtin Interacting Protein HYPK. Gottlieb L, Marmorstein R. Structure 26 925-935.e8 (2018)
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  4. Highly Selective Cleavage of TH2-Promoting Cytokines by the Human and the Mouse Mast Cell Tryptases, Indicating a Potent Negative Feedback Loop on TH2 Immunity. Fu Z, Akula S, Thorpe M, Hellman L. Int J Mol Sci 20 E5147 (2019)
  5. Differential toxicity of ataxin-3 isoforms in Drosophila models of Spinocerebellar Ataxia Type 3. Johnson SL, Blount JR, Libohova K, Ranxhi B, Paulson HL, Tsou WL, Todi SV. Neurobiol Dis 132 104535 (2019)
  6. Impact of Losing hRpn13 Pru or UCHL5 on Proteasome Clearance of Ubiquitinated Proteins and RA190 Cytotoxicity. Osei-Amponsa V, Sridharan V, Tandon M, Evans CN, Klarmann K, Cheng KT, Lack J, Chari R, Walters KJ. Mol Cell Biol 40 e00122-20 (2020)
  7. Structural basis for the recognition of K48-linked Ub chain by proteasomal receptor Rpn13. Liu Z, Dong X, Yi HW, Yang J, Gong Z, Wang Y, Liu K, Zhang WP, Tang C. Cell Discov 5 19 (2019)
  8. An Extended Conformation for K48 Ubiquitin Chains Revealed by the hRpn2:Rpn13:K48-Diubiquitin Structure. Lu X, Ebelle DL, Matsuo H, Walters KJ. Structure 28 495-506.e3 (2020)
  9. Cryo-EM Reveals Unanchored M1-Ubiquitin Chain Binding at hRpn11 of the 26S Proteasome. Chen X, Dorris Z, Shi D, Huang RK, Khant H, Fox T, de Val N, Williams D, Zhang P, Walters KJ. Structure 28 1206-1217.e4 (2020)
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  11. Expression and Regulation of Deubiquitinase-Resistant, Unanchored Ubiquitin Chains in Drosophila. Blount JR, Libohova K, Marsh GB, Sutton JR, Todi SV. Sci Rep 8 8513 (2018)
  12. Phosphorylation of Tyr-950 in the proteasome scaffolding protein RPN2 modulates its interaction with the ubiquitin receptor RPN13. Hemmis CW, Heard SC, Hill CP. J Biol Chem 294 9659-9665 (2019)
  13. Quantitative Proteomic Analysis Reveals That Arctigenin Alleviates Concanavalin A-Induced Hepatitis Through Suppressing Immune System and Regulating Autophagy. Feng Q, Yao J, Zhou G, Xia W, Lyu J, Li X, Zhao T, Zhang G, Zhao N, Yang J. Front Immunol 9 1881 (2018)
  14. Mechanistic Studies of the Multiple Myeloma and Melanoma Cell-Selective Toxicity of the Rpn13-Binding Peptoid KDT-11. Dickson P, Simanski S, Ngundu JM, Kodadek T. Cell Chem Biol 27 1383-1395.e5 (2020)
  15. Proteasomal deubiquitinase UCH37 inhibits degradation of β-catenin and promotes cell proliferation and motility. Li Z, Zhou L, Jiang T, Fan L, Liu X, Qiu X. Acta Biochim Biophys Sin (Shanghai) 51 277-284 (2019)
  16. Structure-function analyses of candidate small molecule RPN13 inhibitors with antitumor properties. Anchoori RK, Tan M, Tseng SH, Peng S, Soong RS, Algethami A, Foran P, Das S, Wang C, Wang TL, Liang H, Hung CF, Roden RBS. PLoS One 15 e0227727 (2020)
  17. Structure-guided bifunctional molecules hit a DEUBAD-lacking hRpn13 species upregulated in multiple myeloma. Lu X, Sabbasani VR, Osei-Amponsa V, Evans CN, King JC, Tarasov SG, Dyba M, Das S, Chan KC, Schwieters CD, Choudhari S, Fromont C, Zhao Y, Tran B, Chen X, Matsuo H, Andresson T, Chari R, Swenson RE, Tarasova NI, Walters KJ. Nat Commun 12 7318 (2021)
  18. 19S Proteasome Subunits as Oncogenes and Prognostic Biomarkers in FLT3-Mutated Acute Myeloid Leukemia (AML). Lara JJ, Bencomo-Alvarez AE, Gonzalez MA, Olivas IM, Young JE, Lopez JL, Velazquez VV, Glovier S, Keivan M, Rubio AJ, Dang SK, Solecki JP, Allen JC, Tapia DN, Tychhon B, Astudillo GE, Jordan C, Chandrashekar DS, Eiring AM. Int J Mol Sci 23 14586 (2022)
  19. Genetic Alterations in Members of the Proteasome 26S Subunit, AAA-ATPase (PSMC) Gene Family in the Light of Proteasome Inhibitor Resistance in Multiple Myeloma. Haertle L, Buenache N, Cuesta Hernández HN, Simicek M, Snaurova R, Rapado I, Martinez N, López-Muñoz N, Sánchez-Pina JM, Munawar U, Han S, Ruiz-Heredia Y, Colmenares R, Gallardo M, Sanchez-Beato M, Piris MA, Samur MK, Munshi NC, Ayala R, Kortüm KM, Barrio S, Martínez-López J. Cancers (Basel) 15 532 (2023)
  20. Proteasome Inhibition Is an Effective Treatment Strategy for Microsporidia Infection in Honey Bees. Huntsman EM, Cho RM, Kogan HV, McNamara-Bordewick NK, Tomko RJ, Snow JW. Biomolecules 11 1600 (2021)
  21. Discovery of a non-covalent ligand for Rpn-13, a therapeutic target for hematological cancers. Loy CA, Muli CS, Ali EMH, Xie D, Ahmed MH, Beth Post C, Trader DJ. Bioorg Med Chem Lett 95 129485 (2023)
  22. The prognostic value of 19S ATPase proteasome subunits in acute myeloid leukemia and other forms of cancer. Tychhon B, Allen JC, Gonzalez MA, Olivas IM, Solecki JP, Keivan M, Velazquez VV, McCall EB, Tapia DN, Rubio AJ, Jordan C, Elliott D, Eiring AM. Front Med (Lausanne) 10 1209425 (2023)


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