Óscar Llorca Group Leader
T +34 (+34) 917 328 000 (Ext 3000)
ollorca@cnio.es

Activation and assembly of many protein complexes implicated in cancer, such as kinases and polymerases, require the assistance of HSP90, a molecular chaperone. Thus, HSP90 inhibitors are being evaluated as anticancer agents.

HSP90 is needed for the activation and stability of the PI3- kinase-like kinases (PIKKs), including mTOR, ATM and ATR that regulate the DNA damage response and cell growth. Surprisingly, these kinases require the action of HSP90 but working in concert with the R2TP/Prefoldin-like (R2TP/ PFDL) complex. R2TP/PFDL is the most complex HSP90 co-chaperone yet described. R2TP/PFDL contains multiple subunits and growing evidence links this complex to cancer.

Yet, how all these processes work is largely unknown. We are using cryo-electron microscopy (cryo-EM) to fully understand the molecular mechanisms of R2TP/PFDL and to bring us a step closer to designing strategies to interfere with PIKK assembly and activation.

Publications

• Famelis N, Rivera-Calzada A, Degliesposti G, Wingender M, Mietrach N, Skehel JM, Fernandez-Leiro R, Böttcher B, Schlosser A, Llorca O, Geibel S (2019). Architecture of the mycobacterial type VII secretion system. Nature (in press). CNIO Publication.
• Serna M (2019). Hands on Methods for High Resolution Cryo-Electron Microscopy Structures of Heterogeneous Macromolecular Complexes.. Front Mol Biosci 6, 33. CNIO Publication. Open Access
• Muñoz-Hernández H, Pal M, Rodríguez CF, Fernandez-Leiro R, Prodromou C, Pearl LH, Llorca O (2019). Structural mechanism for regulation of the AAA-ATPases RUVBL1-RUVBL2 in the R2TP co-chaperone revealed by cryo-EM. Sci Adv 5, eaaw1616. CNIO Publication. Open Access
• Menny A, Serna M, Boyd CM, Gardner S, Joseph AP, Morgan BP, Topf M, Brooks NJ, Bubeck D (2018). CryoEM reveals how the complement membrane attack complex ruptures lipid bilayers. Nat Commun 9, 5316. CNIO Publication. Open Access
• Martino F, Pal M, Muñoz-Hernández H, Rodríguez CF, Núñez-Ramírez R, Gil-Carton D, Degliesposti G, Skehel JM, Roe SM, Prodromou C, Pearl LH, Llorca O (2018). RPAP3 provides a flexible scaffold for coupling HSP90 to the human R2TP co-chaperone complex. Nat Commun 9, 1501. CNIO Publication. Open Access
• de Jorge EG, Yebenes H, Serna M, Tortajada A, Llorca O, de Córdoba SR (2018). How novel structures inform understanding of complement function. Semin Immunopathol 40, 3-14. CNIO Publication.
• Muñoz-Hernández H, Pal M, Rodríguez CF, Prodromou C, Pearl LH, Llorca O (2018). Advances on the Structure of the R2TP/Prefoldin-like Complex. Adv Exp Med Biol 1106, 73-83. CNIO Publication.
• Rivera-Calzada A, Mohinder P, Muñoz-Hernandez H, Luque-Ortega JR, Gil-Carton D, Degliesposti G, Skehel JM, Prodromou C, Pearl LH and Llorca O. (2017). The structure of the R2TP complex defines a platform for recruiting diverse client proteins to the HSP90 molecular chaperone system.. Structure 25, 1145-1152. Publication in other institutions.
• Subías Hidalgo M, Yébenes H, Rodríguez-Gallego C, Martín-Ambrosio A, Domínguez M, Tortajada A, Rodríguez de Córdoba S, Llorca O. (2017). Functional and structural characterization of four mouse monoclonal antibodies to complement C3 with potential therapeutic and diagnostic applications. Eur J Immunol 47, 504-515. Publication in other institutions.
• Huecas S, Ramirez-Aportela E, Vergoños A, Nuñez-Ramirez R, Llorca O, Diaz JF, Juan-Rodríuez J, Oliva MA, Castellen P, Andreu JM (2017). Self-Organization of FtsZ Polymers in Solution Reveals Spacer Role of the Disordered C-Terminal Tail.. Biophys J 113, 1831-1844. CNIO Publication.
• López-Perrote A, Harrison RE, Subías M, Alcorlo M, Rodríguez de Córdoba S, Morikis D, Llorca O. (2017). Ionic tethering contributes to the conformational stability and function of complement C3b.. Mol Immunol 85, 137-147. Publication in other institutions.
• Fernandez-Rodriguez C, Llorca O, Martino F (2017). Transmission Cryo-electron Microscopy in Drug Discovery.Royal Society of Biochemistry.. Biophysical Techniques in Drug Discovery (in press). CNIO Publication.
• Melero R, Hug N, López-Perrote A, Yamashita A, Cáceres JF, Llorca O (2016). The RNA helicase DHX34 functions as a scaffold for SMG1-mediated UPF1 phosphorylation.. Nat Communications 7, 10585. Publication in other institutions.
• López-Perrote A, Castaño R, Melero R, Zamarro T, Kurosawa H, Ohnishi T, Uchiyama A, Aoyagi K, Buchwald G, Kataoka N, Yamashita A, Llorca O. (2016). Human nonsense-mediated mRNA decay factor UPF2 interacts directly with eRF3 and the SURF complex.. Nucleic Acids Res 44, 1909-1923. Publication in other institutions.
• Torreira E, Moreno-Del Álamo M, Fuentes-Perez ME, Fernández C, Martín-Benito J, Moreno-Herrero F, Giraldo R, Llorca O. (2015). Amyloidogenesis of bacterial prionoid RepA-WH1 recapitulates dimer to monomer transitions of RepA in DNA replication initiation.. Structure 23, 183-189. Publication in other institutions.
• Alcorlo M, López-Perrote A, Delgado S, Yébenes H, Subías M, Rodríguez-Gallego C, Rodríguez de Córdoba S, Llorca O. (2015). Structural insights on complement activation.. FEBS J 282, 3883-3891. Publication in other institutions.
• Rivera-Calzada A et al. and Llorca O (2015). Structure and Assembly of the PI3K-like Protein Kinases (PIKKs) Revealed by Electron Microscopy .. AIMS BIOPHYSICS 2, 36-57. Publication in other institutions.
• Melero R, Uchiyama A, Castaño R, Kataoka N, Kurosawa H, Ohno S, Yamashita A, Llorca O. (2014). Structures of SMG1-UPFs complexes: SMG1 contributes to regulate UPF2-dependent activation of UPF1 in NMD.. Structure 22, 1105-1119. Publication in other institutions.
• López-Perrote A, Alatwi HE, Torreira E, Ismail A, Ayora S, Downs JA, Llorca O. (2014). Structure of Yin Yang 1 oligomers that cooperate with RuvBL1-RuvBL2 ATPases.. J Biol Chem 289, 22614-22629. Publication in other institutions.