Macromolecular Complexes in DNA Damage Response Group

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

Staff Scientists

Javier Coloma
Ana I. Hernández
María Ibarra
Andrés López
Ángel Rivera
Marina Serna

Post-Doctoral Fellows

Sofía Cabezudo
María Martínez

Graduate Students

Natalia Cuervo
Nayim González

Technicians

Paloma Escudero
Ana González

Our current work dedicates special attention to study RUVBL1 and RUVBL2, 2 highly conserved AAA+ ATPases that are essential for several cellular processes relevant in cancer, including Fanconi anaemia, chromatin remodelling, nonsense-mediated mRNA decay (NMD), and the assembly and activation of large macromolecular complexes such as the those formed by mTOR and ATR kinases. Interestingly, RUVBL1-RUVBL2 inhibitors show anti-oncogenic potential, and cancer cells with high mTOR activity are dependent on the functions of RUVBL1-RUVBL2 for survival. How RUVBL1 and RUVBL2 perform their functions is only partially understood. Our work provides novel structural and mechanistic understanding of how these ATPases work, which will be useful for exploring new ways to target these proteins. For this, we combine biochemistry, and molecular and cell biology with cryo-electron microscopy methods that allow us to visualise individual macromolecular complexes and to resolve their structure at high resolution.

Publications

Rodriguez CF, Escudero-Bravo P, Díaz L, Bartoccioni P, García-Martín C, Gilabert JG, Boskovic J, Guallar V, Errasti-Murugarren E, Llorca O, Palacín M (2021). Structural basis for substrate specificity of heteromeric transporters of neutral amino acids.. Proc Natl Acad Sci USA 118, e2113573118. CNIO Publication.
Dauden MI, López-Perrote A, Llorca O (2021). RUVBL1-RUVBL2 AAA-ATPase: a versatile scaffold for multiple complexes and functions. Curr Opin Struc Biol 19, 78-85. CNIO Publication.
Fresno C, García-Arriaza J, Martínez-Cano S, Heras-Murillo I, Jarit-Cabanillas A, Amores-Iniesta J, Brandi P, Dunphy G, Suay-Corredera S, Pricolo MR, Vicente N, López-Perrote A, Cabezudo S, González-Corpas A, LLorca O, Alegre-Cebollada J, Garaigorta U, Gastamiza P, Esteban M, Sancho D (2021). The Bacterial Mucosal Immunotherapy MV130 Protects Against SARS-CoV-2 Infection and Improves COVID-19 Vaccines Immunogenicity. Front Inmmunol (in press). CNIO Publication.
Pal M, Muñoz-Hernandez H, Bjorklund D, Zhou L, Degliesposti G, Skehel JM, Hesketh EL, Thompson RF, Pearl LH, Llorca O, Prodromou C (2021). Structure of the TELO2-TTI1-TTI2 complex and its function in TOR recruitment to the R2TP chaperone. Cell Reports 36, 109317. CNIO Publication.
Unfried JP, Marín-Baquero M, Rivera-Calzada Á, Razquin N, Martín-Cuevas EM, de Bragança S, Aicart-Ramos C, McCoy C, Prats-Mari L, Arribas-Bosacoma R, Lee L, Caruso S, Zucman-Rossi J, Sangro B, Williams G, Moreno-Herrero F, Llorca O, Lees-Miller SP, Fortes P (2021). Long noncoding RNA NIHCOLE promotes ligation efficiency of DNA double-strand breaks in hepatocellular carcinoma.. Cancer Res 81, 4910-4925. CNIO Publication.
Serna M, González-Corpas A, Cabezudo S, López-Perrote A, Degliesposti G, Zarzuela E, Skehel JM, Muñoz J, Llorca O (2021). CryoEM of RUVBL1-RUVBL2-ZNHIT2, a complex that interacts with pre-mRNA-processing-splicing factor 8. Nucleic Acids Res (in press). CNIO Publication.
Rivera Calzada A, Famelis Nikolaos, Llorca O, Geibel S (2021). Type VII secretion systems: structure, functions and transport models. Nat Rev Microbiol 19, 567-584. CNIO Publication.
Rodríguez Carlos F, LLorca O (2020). RPAP3 C-Terminal Domain: A Conserved Domain for the Assembly of R2TP Co-Chaperone Complexes. Cells 9, E1139. CNIO Publication.
López-Perrote A , NHug N, González-Corpas A, Rodríguez CF , Serna M, García-Martín C , Boskovic J, Fernandez-Leiro R, Caceres JF , Llorca O (2020). Regulation of RUVBL1-RUVBL2 AAA-ATPases by the nonsense-mediated mRNA decay factor DHX34, as evidenced by Cryo-EM. Elife 9, e63042. CNIO Publication. Open Access
Dauden M, López-Perrote A, Llorca O (2020). RUVBL1–RUVBL2 AAA-ATPase: a versatile scaffold for multiple complexes and functions. Curr Opin Struc Biol 67, 78-85. CNIO Publication.
Zimmermann F, Serna M, Ezquerra A, Fernandez-Leiro R, Llorca O, Luders J (2020). Assembly of the asymmetric human ?-tubulin ring complex by RUVBL1-RUVBL2 AAA ATPase. Sci Adv 6, eabe0894. CNIO Publication.
Rodríguez CF, Pal M, Muñoz-Hernandez H, Pearl LH, Llorca O (2020). Modeling of a 14 kDa RUVBL2-Binding Domain with Medium Resolution Cryo-EM Density.. J Chem Inf Model 60, 2541-2551. CNIO Publication.
Acebrón I, Righetto RD, Schoenherr C, Buhr S, Redondo P, Culley J, Rodríguez CF, Daday C, Biyani N, Llorca O, Byron A, Chami M, Gräter F, Boskovic J, Margaret C Frame, Stahlberg H, Lietha D (2020). Structural basis of Focal Adhesion Kinase activation on lipid membranes.. EMBO J 39, e104743. CNIO Publication.
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 576, 321-325. 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
Rivera-Calzada A, Carroni M (2019). Editorial: Technical Advances in Cryo-Electron Microscopy.. Front Mol Biosci 6, 72. 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.