Advertisement

Advances on the Structure of the R2TP/Prefoldin-like Complex

  • Hugo Muñoz-Hernández
  • Mohinder Pal
  • Carlos F. Rodríguez
  • Chrisostomos Prodromou
  • Laurence H. Pearl
  • Oscar LlorcaEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1106)

Abstract

Cellular stability, assembly and activation of a growing list of macromolecular complexes require the action of HSP90 working in concert with the R2TP/Prefoldin-like (R2TP/PFDL) co-chaperone. RNA polymerase II, snoRNPs and complexes of PI3-kinase-like kinases, a family that includes the ATM, ATR, DNA-PKcs, TRAPP, SMG1 and mTOR proteins, are among the clients of the HSP90-R2TP system. Evidence links the R2TP/PFDL pathway with cancer, most likely because of the essential role in pathways commonly deregulated in cancer. R2TP forms the core of the co-cochaperone and orchestrates the recruitment of HSP90 and clients, whereas prefoldin and additional prefoldin-like proteins, including URI, associate with R2TP, but their function is still unclear. The mechanism by which R2TP/PFLD facilitates assembly and activation of such a variety of macromolecular complexes is poorly understood. Recent efforts in the structural characterization of R2TP have started to provide some mechanistic insights. We summarize recent structural findings, particularly how cryo-electron microscopy (cryo-EM) is contributing to our understanding of the architecture of the R2TP core complex. Structural differences discovered between yeast and human R2TP reveal unanticipated complexities of the metazoan R2TP complex, and opens new and interesting questions about how R2TP/PFLD works.

Keywords

R2TP Prefoldin HSP90 Co-chaperone cryo-EM PIH1D1 RPAP3 RUVBL1 RUVBL2 TTT TELO2-TTI1-TTI2 complex Pih1 Tah1 Rvb1 Rvb2 

Notes

Acknowledgements

This work was supported by the Project EXCELENCIA SAF2017-82632-P, MCIU-AEI and cofounded by the European Regional Development fund (ERDF-EU) to OL and BES-2015-071348 to CFR. We thank Lidia Cerdán (CNB-CSIC) for help in Fig. 5.4.

Competing Financial Interests

The authors declare no competing financial interests.

References

  1. Ayala R, Willhoft O, Aramayo RJ, Wilkinson M, McCormack EA, Ocloo L et al (2018) Structure and regulation of the human INO80-nucleosome complex. Nature 556(7701):391–395CrossRefGoogle Scholar
  2. Back R, Dominguez C, Rothe B, Bobo C, Beaufils C, Morera S et al (2013) High-resolution structural analysis shows how Tah1 tethers Hsp90 to the R2TP complex. Structure 21(10):1834–1847CrossRefGoogle Scholar
  3. Boulon S, Pradet-Balade B, Verheggen C, Molle D, Boireau S, Georgieva M et al (2010) HSP90 and its R2TP/Prefoldin-like cochaperone are involved in the cytoplasmic assembly of RNA polymerase II. Mol Cell 39(6):912–924CrossRefGoogle Scholar
  4. Buren S, Gomes AL, Teijeiro A, Fawal MA, Yilmaz M, Tummala KS et al (2016) Regulation of OGT by URI in Response to Glucose Confers c-MYC-Dependent Survival Mechanisms. Cancer Cell 30(2):290–307CrossRefGoogle Scholar
  5. Cheung KL, Huen J, Houry WA, Ortega J (2010) Comparison of the multiple oligomeric structures observed for the Rvb1 and Rvb2 proteins. Biochem Cell Biol 88(1):77–88CrossRefGoogle Scholar
  6. Cloutier P, Al-Khoury R, Lavallee-Adam M, Faubert D, Jiang H, Poitras C et al (2009) High-resolution mapping of the protein interaction network for the human transcription machinery and affinity purification of RNA polymerase II-associated complexes. Methods 48(4):381–386CrossRefGoogle Scholar
  7. Cloutier P, Poitras C, Durand M, Hekmat O, Fiola-Masson E, Bouchard A et al (2017) R2TP/Prefoldin-like component RUVBL1/RUVBL2 directly interacts with ZNHIT2 to regulate assembly of U5 small nuclear ribonucleoprotein. Nat Commun 8:15615CrossRefGoogle Scholar
  8. Eckert K, Saliou JM, Monlezun L, Vigouroux A, Atmane N, Caillat C et al (2010) The Pih1-Tah1 cochaperone complex inhibits Hsp90 molecular chaperone ATPase activity. J Biol Chem 285(41):31304–31312CrossRefGoogle Scholar
  9. Eustermann S, Schall K, Kostrewa D, Lakomek K, Strauss M, Moldt M et al (2018) Structural basis for ATP-dependent chromatin remodelling by the INO80 complex. Nature 556(7701):386–390CrossRefGoogle Scholar
  10. Ewens CA, Su M, Zhao L, Nano N, Houry WA, Southworth DR (2016) Architecture and Nucleotide-Dependent Conformational Changes of the Rvb1-Rvb2 AAA+ Complex Revealed by Cryoelectron Microscopy. Structure 24(5):657–666CrossRefGoogle Scholar
  11. Feng SW, Chen Y, Tsai WC, Chiou HC, Wu ST, Huang LC et al (2016) Overexpression of TELO2 decreases survival in human high-grade gliomas. Oncotarget 7(29):46056–46066CrossRefGoogle Scholar
  12. Gorynia S, Bandeiras TM, Pinho FG, McVey CE, Vonrhein C, Round A et al (2011) Structural and functional insights into a dodecameric molecular machine – the RuvBL1/RuvBL2 complex. J Struct Biol 176(3):279–291CrossRefGoogle Scholar
  13. Horejsi Z, Takai H, Adelman CA, Collis SJ, Flynn H, Maslen S et al (2010) CK2 phospho-dependent binding of R2TP complex to TEL2 is essential for mTOR and SMG1 stability. Mol Cell 39(6):839–850CrossRefGoogle Scholar
  14. Horejsi Z, Stach L, Flower TG, Joshi D, Flynn H, Skehel JM et al (2014) Phosphorylation-dependent PIH1D1 interactions define substrate specificity of the R2TP cochaperone complex. Cell Rep 7(1):19–26CrossRefGoogle Scholar
  15. Houry WA, Bertrand E, Coulombe B (2018) The PAQosome, an R2TP-Based Chaperone for Quaternary Structure Formation. Trends Biochem Sci 43(1):4–9CrossRefGoogle Scholar
  16. Huber O, Menard L, Haurie V, Nicou A, Taras D, Rosenbaum J (2008) Pontin and reptin, two related ATPases with multiple roles in cancer. Cancer Res 68(17):6873–6876CrossRefGoogle Scholar
  17. Imseng S, Aylett CH, Maier T (2018) Architecture and activation of phosphatidylinositol 3-kinase related kinases. Curr Opin Struct Biol 49:177–189CrossRefGoogle Scholar
  18. Itsuki Y, Saeki M, Nakahara H, Egusa H, Irie Y, Terao Y et al (2008) Molecular cloning of novel Monad binding protein containing tetratricopeptide repeat domains. FEBS Lett 582(16):2365–2370CrossRefGoogle Scholar
  19. Jeronimo C, Forget D, Bouchard A, Li Q, Chua G, Poitras C et al (2007) Systematic analysis of the protein interaction network for the human transcription machinery reveals the identity of the 7SK capping enzyme. Mol Cell 27(2):262–274CrossRefGoogle Scholar
  20. Jimenez B, Ugwu F, Zhao R, Orti L, Makhnevych T, Pineda-Lucena A et al (2012) Structure of minimal tetratricopeptide repeat domain protein Tah1 reveals mechanism of its interaction with Pih1 and Hsp90. J Biol Chem 287(8):5698–5709CrossRefGoogle Scholar
  21. Kakihara Y, Houry WA (2012) The R2TP complex: discovery and functions. Biochim Biophys Acta 1823(1):101–107CrossRefGoogle Scholar
  22. Kakihara Y, Saeki M (2014) The R2TP chaperone complex: its involvement in snoRNP assembly and tumorigenesis. Biomol Concepts 5(6):513–520CrossRefGoogle Scholar
  23. Kim SG, Hoffman GR, Poulogiannis G, Buel GR, Jang YJ, Lee KW et al (2013) Metabolic stress controls mTORC1 lysosomal localization and dimerization by regulating the TTT-RUVBL1/2 complex. Mol Cell 49(1):172–185CrossRefGoogle Scholar
  24. Lakomek K, Stoehr G, Tosi A, Schmailzl M, Hopfner KP (2015) Structural basis for dodecameric assembly states and conformational plasticity of the full-length AAA+ ATPases Rvb1 . Rvb2. Structure 23(3):483–495CrossRefGoogle Scholar
  25. Lopez-Perrote A, Munoz-Hernandez H, Gil D, Llorca O (2012) Conformational transitions regulate the exposure of a DNA-binding domain in the RuvBL1-RuvBL2 complex. Nucleic Acids Res 40(21):11086–11099CrossRefGoogle Scholar
  26. Machado-Pinilla R, Liger D, Leulliot N, Meier UT (2012) Mechanism of the AAA+ ATPases pontin and reptin in the biogenesis of H/ACA RNPs. RNA 18(10):1833–1845CrossRefGoogle Scholar
  27. Martino F, Pal M, Munoz-Hernandez H, Rodriguez CF, Nunez-Ramirez R, Gil-Carton D et al (2018) RPAP3 provides a flexible scaffold for coupling HSP90 to the human R2TP co-chaperone complex. Nat Commun 9(1):1501CrossRefGoogle Scholar
  28. Maurizy C, Quinternet M, Abel Y, Verheggen C, Santo PE, Bourguet M et al (2018) The RPAP3-Cterminal domain identifies R2TP-like quaternary chaperones. Nat Commun 9(1):2093CrossRefGoogle Scholar
  29. Millson SH, Vaughan CK, Zhai C, Ali MM, Panaretou B, Piper PW et al (2008) Chaperone ligand-discrimination by the TPR-domain protein Tah1. Biochem J 413(2):261–268CrossRefGoogle Scholar
  30. Mita P, Savas JN, Ha S, Djouder N, Yates JR 3rd, Logan SK (2013) Analysis of URI nuclear interaction with RPB5 and components of the R2TP/prefoldin-like complex. PLoS One 8(5):e63879CrossRefGoogle Scholar
  31. Morgan RM, Pal M, Roe SM, Pearl LH, Prodromou C (2015) Tah1 helix-swap dimerization prevents mixed Hsp90 co-chaperone complexes. Acta Crystallogr D Biol Crystallogr 71(Pt 5):1197–1206CrossRefGoogle Scholar
  32. Olcese C, Patel MP, Shoemark A, Kiviluoto S, Legendre M, Williams HJ et al (2017) X-linked primary ciliary dyskinesia due to mutations in the cytoplasmic axonemal dynein assembly factor PIH1D3. Nat Commun 8:14279CrossRefGoogle Scholar
  33. Pal M, Morgan M, Phelps SE, Roe SM, Parry-Morris S, Downs JA et al (2014) Structural basis for phosphorylation-dependent recruitment of Tel2 to Hsp90 by Pih1. Structure 22(6):805–818CrossRefGoogle Scholar
  34. Prodromou C (2012) The ‘active life’ of Hsp90 complexes. Biochim Biophys Acta 1823(3):614–623CrossRefGoogle Scholar
  35. Rivera-Calzada A, Pal M, Munoz-Hernandez H, Luque-Ortega JR, Gil-Carton D, Degliesposti G et al (2017) The structure of the R2TP complex defines a platform for recruiting diverse client proteins to the HSP90 molecular chaperone system. Structure 25(7):1145–1152 e4CrossRefGoogle Scholar
  36. Saeki M, Egusa H, Kamano Y, Kakihara Y, Houry WA, Yatani H et al (2013) Exosome-bound WD repeat protein Monad inhibits breast cancer cell invasion by degrading amphiregulin mRNA. PLoS One 8(7):e67326CrossRefGoogle Scholar
  37. Sang Y, Chen MY, Luo D, Zhang RH, Wang L, Li M et al (2015) TEL2 suppresses metastasis by down-regulating SERPINE1 in nasopharyngeal carcinoma. Oncotarget 6(30):29240–29253CrossRefGoogle Scholar
  38. Takai H, Xie Y, de Lange T, Pavletich NP (2010) Tel2 structure and function in the Hsp90-dependent maturation of mTOR and ATR complexes. Genes Dev 24(18):2019–2030CrossRefGoogle Scholar
  39. Tian S, Yu G, He H, Zhao Y, Liu P, Marshall AG et al (2017) Pih1p-Tah1p puts a lid on hexameric AAA+ ATPases Rvb1/2p. Structure 25(10):1519–1529 e4CrossRefGoogle Scholar
  40. Torreira E, Jha S, Lopez-Blanco JR, Arias-Palomo E, Chacon P, Canas C et al (2008) Architecture of the pontin/reptin complex, essential in the assembly of several macromolecular complexes. Structure 16(10):1511–1520CrossRefGoogle Scholar
  41. Tummala KS, Gomes AL, Yilmaz M, Grana O, Bakiri L, Ruppen I et al (2014) Inhibition of de novo NAD(+) synthesis by oncogenic URI causes liver tumorigenesis through DNA damage. Cancer Cell 26(6):826–839CrossRefGoogle Scholar
  42. Vaughan CK (2014) Hsp90 picks PIKKs via R2TP and Tel2. Structure 22(6):799–800CrossRefGoogle Scholar
  43. von Morgen P, Burdova K, Flower TG, O’Reilly NJ, Boulton SJ, Smerdon SJ et al (2017) MRE11 stability is regulated by CK2-dependent interaction with R2TP complex. Oncogene 36(34):4943–4950CrossRefGoogle Scholar
  44. Zhao R, Kakihara Y, Gribun A, Huen J, Yang G, Khanna M et al (2008) Molecular chaperone Hsp90 stabilizes Pih1/Nop17 to maintain R2TP complex activity that regulates snoRNA accumulation. J Cell Biol 180(3):563–578CrossRefGoogle Scholar
  45. Zur Lage P, Stefanopoulou P, Styczynska-Soczka K, Quinn N, Mali G, von Kriegsheim A et al (2018) Ciliary dynein motor preassembly is regulated by Wdr92 in association with HSP90 co-chaperone, R2TP. J Cell Biol 217:2583–2598CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Hugo Muñoz-Hernández
    • 1
  • Mohinder Pal
    • 2
  • Carlos F. Rodríguez
    • 1
  • Chrisostomos Prodromou
    • 2
  • Laurence H. Pearl
    • 2
  • Oscar Llorca
    • 1
    Email author
  1. 1.Spanish National Cancer Research Centre (CNIO)MadridSpain
  2. 2.Genome Damage and Stability Centre, School of Life SciencesUniversity of SussexBrightonUK

Personalised recommendations