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

• Serna M (2019). Hands on Methods for High Resolution Cryo-Electron Microscopy Structures of Heterogeneous Macromolecular Complexes.. Front Mol Biosci 6, 33. 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 (in press). 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. 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. 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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).
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Alcorlo M, Tortajada A, Rodríguez de Córdoba S, Llorca O. (2013). Structural basis for the stabilization of the complement alternative pathway C3 convertase by properdin.. Proc Natl Acad Sci USA 110, 13504-13509.
• Llorca O (2013). Structural insights into nonsense-mediated mRNA decay (NMD) by electron microscopy.. Curr Opin Struc Biol 23, 161-167.