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Institute for Research in Biomedicine
Istituto di Ricerca in Biomedicina

Via Vincenzo Vela 6 - CH-6500 Bellinzona
Tel. +41 91 820 0300 - Fax +41 91 820 0302 - info [at] irb [dot] usi [dot] ch

Luca Varani, PhD

Structural Biology

Group Leader

Via Vela, 6
6500 Bellinzona, Switzerland

Luca Varani
Bio

Luca Varani graduated in chemistry at the University of Milan (Italy) and obtained a PhD degree at the prestigious MRC-Laboratory of Molecular Biology (University of Cambridge, UK) using molecular and structural biology to study RNA-protein interactions. He contributed to show the key role played by RNA in regulation of gene expression and how RNA itself can be a valid therapeutic target against dementia. His numerous high caliber publications, culminated in the determination of the largest NMR structure available at the time, allowed him to move to Stanford with a “long term EMBO fellowship”, reserved to the best young molecular biologists in Europe. In California Luca Varani completed the first magnetic resonance study on TCR/pMHC, key proteins of the immune system.

Since October 2007 he leads the Structural Biology group of the Institute for Research in Biomedicine (Bellinzona, CH). The main activity involves the characterization of interactions between pathogens and antibodies, molecules of the immune system capable of curing and protecting from illness. The group tries to understand the molecular properties that allow a given antibody to eliminate a pathogen. Studies involve mainly rare and neglected diseases such as Dengue or Zika virus, Prion or rare form of Leukemias. The NMR approach developed at Stanford was pushed forward at the IRB, where computational techniques allow discovering which part of the pathogen is recognized by antibodies. Experimentally guided and validated computational simulations yield the atomic three-dimensional structure of antibody/pathogen complexes. The approach allowed to rationally modify an existing antibody, increasing its ability to neutralize Dengue virus by 50 fold utilizing, for the first time, only computational tools. They also performed one of the rare NMR studies showing how antibody binding alter the local flexibility of the antigen. 

The group uses a highly multidisciplinary approach, varying from structure determination to cellular experiments, from computational biology to protein and antibody production and engineering, from synthesis of nanoparticles to confocal microscopy.

Projects
Investigating the role of Interleukin 3 and TIM3 for the detection and elimination of Acute Mieloid Leukemia
RADAR: Rationally Designed Aquatic Receptors for the detection of organic pollutants
Prediction and characterization of antibody-protein interactions in Dengue virus
Characterization of antibody-protein interactions in Diphtheria Toxin
Publications
A bispecific immunotweezer prevents soluble PrP oligomers and abolishes prion toxicity
M. Bardelli, K. Frontzek, L. Simonelli, S. Hornemann, M. Pedotti, F. Mazzola, M. Carta, V. Eckhardt, R. D'Antuono, T. Virgilio, S. F. Gonzalez, A. Aguzzi, L. Varani
in PLoS Pathog (2018) vol. 14 ppe1007335
Mapping Antibody Epitopes by Solution NMR Spectroscopy: Practical Considerations
L. Simonelli, M. Pedotti, M. Bardelli, S. Jurt, O. Zerbe, L. Varani
in Methods Mol Biol (2018) vol. 1785 pp29-51
A public antibody lineage that potently inhibits malaria infection through dual binding to the circumsporozoite protein
J. Tan, B. K. Sack, D. Oyen, I. Zenklusen, L. Piccoli, S. Barbieri, M. Foglierini, C. S. Fregni, J. Marcandalli, S. Jongo, S. Abdulla, L. Perez, G. Corradin, L. Varani, F. Sallusto, B. K. L. Sim, S. L. Hoffman, S. H. I. Kappe, C. Daubenberger, I. A. Wilson, A. Lanzavecchia
in Nat Med (2018) vol. 24 pp401-407
Highly specific targeting of human acute myeloid leukaemia cells using pharmacologically active nanoconjugates
I. M. Yasinska, G. Ceccone, I. Ojea-Jimenez, J. Ponti, R. Hussain, G. Siligardi, S. M. Berger, E. Fasler-Kan, M. Bardelli, L. Varani, W. Fiedler, J. Wellbrock, U. Raap, B. F. Gibbs, L. Calzolai, V. V. Sumbayev
in Nanoscale (2018) vol. 10 pp5827-5833
High mobility group box 1 (HMGB1) acts as an "alarmin" to promote acute myeloid leukaemia progression
I. M. Yasinska, I. Goncalves Silva, S. S. Sakhnevych, L. Ruegg, R. Hussain, G. Siligardi, W. Fiedler, J. Wellbrock, M. Bardelli, L. Varani, U. Raap, S. Berger, B. F. Gibbs, E. Fasler-Kan, V. V. Sumbayev
in Oncoimmunology (2018) vol. 7 ppe1438109
Label-Free Biosensor Detection of Endocrine Disrupting Compounds Using Engineered Estrogen Receptors
R. La Spina, V. E. V. Ferrero, V. Aiello, M. Pedotti, L. Varani, T. Lettieri, L. Calzolai, W. Haasnoot, P. Colpo
in Biosensors (Basel) (2017) vol. 8
A Human Bi-specific Antibody against Zika Virus with High Therapeutic Potential
J. Wang, M. Bardelli, D. A. Espinosa, M. Pedotti, T. S. Ng, S. Bianchi, L. Simonelli, E. X. Y. Lim, M. Foglierini, F. Zatta, S. Jaconi, M. Beltramello, E. Cameroni, G. Fibriansah, J. Shi, T. Barca, I. Pagani, A. Rubio, V. Broccoli, E. Vicenzi, V. Graham, S. Pullan, S. Dowall, R. Hewson, S. Jurt, O. Zerbe, K. Stettler, A. Lanzavecchia, F. Sallusto, A. Cavalli, E. Harris, S. M. Lok, L. Varani, D. Corti
in Cell (2017) vol. 171 pp229-241 e15
* J. Wang and M. Bardelli contributed equally ; S-M Lok, L.Varani and D. Corti contributed equally.
The Tim-3-galectin-9 Secretory Pathway is Involved in the Immune Escape of Human Acute Myeloid Leukemia Cells
I. Goncalves Silva, I. M. Yasinska, S. S. Sakhnevych, W. Fiedler, J. Wellbrock, M. Bardelli, L. Varani, R. Hussain, G. Siligardi, G. Ceccone, S. M. Berger, Y. A. Ushkaryov, B. F. Gibbs, E. Fasler-Kan, V. V. Sumbayev
in EBioMedicine (2017) pp44-57
Balance of Anti-CD123 Chimeric Antigen Receptor Binding Affinity and Density for the Targeting of Acute Myeloid Leukemia
S. Arcangeli, M. C. Rotiroti, M. Bardelli, L. Simonelli, C. F. Magnani, A. Biondi, E. Biagi, S. Tettamanti, L. Varani
in Mol Ther (2017) vol. 25 pp1933-1945
Translocon component Sec62 acts in endoplasmic reticulum turnover during stress recovery
F. Fumagalli, J. Noack, T. J. Bergmann, E. C. Presmanes, G. B. Pisoni, E. Fasana, I. Fregno, C. Galli, M. Loi, T. Solda, R. D'Antuono, A. Raimondi, M. Jung, A. Melnyk, S. Schorr, A. Schreiber, L. Simonelli, L. Varani, C. Wilson-Zbinden, O. Zerbe, K. Hofmann, M. Peter, M. Quadroni, R. Zimmermann, M. Molinari
in Nat Cell Biol (2016) vol. 18 pp1173-1184
Fumagalli, F. , Noack J. and Bergmann T. contributed equally to this work. * Recommended by the Faculty of 1000
Specificity, cross-reactivity and function of antibodies elicited by Zika virus infection
K. Stettler, M. Beltramello, D. A. Espinosa, V. Graham, A. Cassotta, S. Bianchi, F. Vanzetta, A. Minola, S. Jaconi, F. Mele, M. Foglierini, M. Pedotti, L. Simonelli, S. Dowall, B. Atkinson, E. Percivalle, C. P. Simmons, L. Varani, J. Blum, F. Baldanti, E. Cameroni, R. Hewson, E. Harris, A. Lanzavecchia, F. Sallusto, D. Corti
in Science (2016) vol. 353 pp823-6
K. S and M. B contributed equally to this work; D. A. E. ; V. G. ; A. C. ; S. B. and F. V contributed equally to this work; F. S. and D. C contributed equally to this work and are co-corresponding authors.
The immune receptor Tim-3 acts as a trafficker in a Tim-3/galectin-9 autocrine loop in human myeloid leukemia cells
I. Goncalves Silva, L. Ruegg, B. F. Gibbs, M. Bardelli, A. Fruehwirth, L. Varani, S. M. Berger, E. Fasler-Kan, V. V. Sumbayev
in Oncoimmunology (2016) vol. 5 ppe1195535
Interleukin-1 beta induces the expression and production of stem cell factor by epithelial cells: crucial involvement of the PI-3K/mTOR pathway and HIF-1 transcription complex
R. W. Wyszynski, B. F. Gibbs, L. Varani, D. Iannotta, V. V. Sumbayev
in Cell Mol Immunol (2016) vol. 13 pp47-56
Antibody Binding Modulates Conformational Exchange in Domain III of Dengue Virus E Protein
A. H. Moraes, L. Simonelli, M. Pedotti, F. C. Almeida, L. * Varani, A. P. Valente
in J Virol (2015) vol. 90 pp1802-11
* Co-corresponding author
Differential expression and biochemical activity of the immune receptor Tim-3 in healthy and malignant human myeloid cells
I. Goncalves Silva, B. F. Gibbs, M. Bardelli, L. * Varani, V. V. Sumbayev
in Oncotarget (2015) vol. 6 pp33823-33
* Co-corresponding author
Prophylactic and postexposure efficacy of a potent human monoclonal antibody against MERS coronavirus
D. Corti, J. Zhao, M. Pedotti, L. Simonelli, S. Agnihothram, C. Fett, B. Fernandez-Rodriguez, M. Foglierini, G. Agatic, F. Vanzetta, R. Gopal, C. J. Langrish, N. A. Barrett, F. Sallusto, R. S. Baric, L. Varani, M. Zambon, S. Perlman, A. Lanzavecchia
in Proc Natl Acad Sci U S A (2015) vol. 112 pp10473-8
D.C. and J.Z. contributed equally to this work.
Epitope mapping by solution NMR spectroscopy
M. Bardelli, E. Livoti, L. Simonelli, M. Pedotti, A. Moraes, A. P. Valente, L. Varani
in J Mol Recognit (2015) vol. 28 pp393-400
Rationally Modified Estrogen Receptor Protein as a Bio-Recognition Element for the Detection of EDC Pollutants: Strategies and Opportunities
M. Pedotti, V. E. Ferrero, T. Lettieri, P. Colpo, S. Follonier, L. Calzolai, L. Varani
in Int J Environ Res Public Health (2015) vol. 12 pp2612-21
The immune receptor Tim-3 mediates activation of PI3 kinase/mTOR and HIF-1 pathways in human myeloid leukaemia cells
A. Prokhorov, B. F. Gibbs, M. Bardelli, L. Ruegg, E. Fasler-Kan, L. * Varani, V. V. Sumbayev
in Int J Biochem Cell Biol (2014) vol. 59C pp11-20
* Co-last and co-corresponding author
Rational modification of estrogen receptor by combination of computational and experimental analysis
V. E. Ferrero, M. Pedotti, A. Chiadò, L. Simonelli, L. Calzolai, T. Lettieri, L. Varani
in PLoS One (2014) vol. 9 ppe102658
Opening Study on the Development of a New Biosensor for Metal Toxicity Based on Pseudomonas fluorescens Pyoverdine
A. Chiadò, L. Varani, F. Bosco, L. Marmo
in Biosensors in Environmental Studies (2013) vol. 4 pp385-99
Receptor-based high-throughput screening and identification of estrogens in dietary supplements using bioaffinity liquid-chromatography ion mobility mass spectrometry
P. Aqai, N. G. Blesa, H. Major, M. Pedotti, L. Varani, V. E. Ferrero, W. Haasnoot, M. W. Nielen
in Anal Bioanal Chem (2013) vol. 405 pp9427-36
Rational Engineering of a Human Anti-Dengue Antibody through Experimentally Validated Computational Docking
L. Simonelli, M. Pedotti, M. Beltramello, E. Livoti, L. Calzolai, F. Sallusto, A. Lanzavecchia, L. Varani
in PLoS One (2013) vol. 8 ppe55561
Luca Simonelli, Mattia Pedotti contributed equally to this work.
Gold nanoparticles downregulate interleukin-1beta-induced pro-inflammatory responses
V. V. Sumbayev, I. M. Yasinska, C. P. Garcia, D. Gilliland, G. S. Lall, B. F. Gibbs, D. R. Bonsall, L. Varani, F. Rossi, L. Calzolai
in Small (2013) vol. 9 pp472-7
Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release
E. Venereau, M. Casalgrandi, M. Schiraldi, D. J. Antoine, A. Cattaneo, F. De Marchis, J. Liu, A. Antonelli, A. Preti, L. Raeli, S. S. Shams, H. Yang, L. Varani, U. Andersson, K. J. Tracey, A. Bachi, M. Uguccioni, M. E. Bianchi
in J Exp Med (2012) vol. 209 pp1519-28
HMGB1 promotes recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling via CXCR4
M. Schiraldi, A. Raucci, L. M. Munoz, E. Livoti, B. Celona, E. Venereau, T. Apuzzo, F. De Marchis, M. Pedotti, A. Bachi, M. Thelen, L. Varani, M. Mellado, A. Proudfoot, M. E. Bianchi, M. Uguccioni
in J Exp Med (2012) vol. 209 pp551-63
* Highlights, Nat. Rev. Immunol. 2012, 12:232
Computational docking of antibody-antigen complexes, opportunities and pitfalls illustrated by influenza hemagglutinin
M. Pedotti, L. Simonelli, E. Livoti, L. Varani
in Int J Mol Sci (2011) vol. 12 pp226-51
The human immune response to Dengue virus is dominated by highly cross-reactive antibodies endowed with neutralizing and enhancing activity
M. Beltramello, K. L. Williams, C. P. Simmons, A. Macagno, L. Simonelli, N. T. Quyen, S. Sukupolvi-Petty, E. Navarro-Sanchez, P. R. Young, A. M. de Silva, F. A. Rey, L. Varani, S. S. Whitehead, M. S. Diamond, E. Harris, A. Lanzavecchia, F. Sallusto
in Cell Host Microbe (2010) vol. 8 pp271-83
Antonio Lanzavecchia and Federica Sallusto are co-corresponding authors.
Rapid structural characterization of human antibody-antigen complexes through experimentally validated computational docking
L. Simonelli, M. Beltramello, Z. Yudina, A. Macagno, L. Calzolai, L. Varani
in J Mol Biol (2010) vol. 396 pp1491-507
The Diversity of Nuclear Magnetic Resonance Spectroscopy
C. W. Liu, V. Y. Alekseyev, J. R. Allwardt, A. J. Bankovich, B. J. Cade-Menun, R. W. Davis, L. S. Du, K. C. Garcia, D. Herschlag, C. Khosla, D. A. Kraut, Q. Li, B. Null, J. D. Puglisi, P. A. Sigala, J. F. Stebbins, L. Varani
in Biophysics and the Challenges of Emerging Threats (2009) pp65-81
Solution mapping of T cell receptor docking footprints on peptide-MHC
L. Varani, A. J. Bankovich, C. W. Liu, L. A. Colf, L. L. Jones, D. M. Kranz, J. D. Puglisi, K. C. Garcia
in Proc Natl Acad Sci U S A (2007) vol. 104 pp13080-5
Elucidation of the interleukin-15 binding site on its alpha receptor by NMR
N. A. Hanick, M. Rickert, L. Varani, A. J. Bankovich, J. R. Cochran, D. M. Kim, C. D. Surh, K. C. Garcia
in Biochemistry (2007) vol. 46 pp9453-61
Nuclear magnetic resonance methods to study structure and dynamics of RNA-protein complexes
M. Allen, L. Varani, G. Varani
in Methods Enzymol (2001) vol. 339 pp357-76
Nuclear magnetic resonance methods to study RNA-protein complexes
P. Bayer, L. Varani, G. Varani
in Methods Enzymol (2000) vol. 317 pp198-220
A novel mutation at position +12 in the intron following exon 10 of the tau gene in familial frontotemporal dementia (FTD-Kumamoto)
M. Yasuda, J. Takamatsu, I. D'Souza, R. A. Crowther, T. Kawamata, M. Hasegawa, H. Hasegawa, M. G. Spillantini, S. Tanimukai, P. Poorkaj, L. Varani, G. Varani, T. Iwatsubo, M. Goedert, D. G. Schellenberg, C. Tanaka
in Ann Neurol (2000) vol. 47 pp422-9
The NMR structure of the 38 kDa U1A protein - PIE RNA complex reveals the basis of cooperativity in regulation of polyadenylation by human U1A protein
L. Varani, S. I. Gunderson, I. W. Mattaj, L. E. Kay, D. Neuhaus, G. Varani
in Nat Struct Biol (2000) vol. 7 pp329-35
Structural basis for recognition of the RNA major groove in the tau exon 10 splicing regulatory element by aminoglycoside antibiotics
L. Varani, M. G. Spillantini, M. Goedert, G. Varani
in Nucleic Acids Res (2000) vol. 28 pp710-9
Changes in side-chain and backbone dynamics identify determinants of specificity in RNA recognition by human U1A protein
A. Mittermaier, L. Varani, D. R. Muhandiram, L. E. Kay, G. Varani
in J Mol Biol (1999) vol. 294 pp967-79
Refinement of the structure of protein-RNA complexes by residual dipolar coupling analysis
P. Bayer, L. Varani, G. Varani
in J Biomol NMR (1999) vol. 14 pp149-55
Structure of tau exon 10 splicing regulatory element RNA and destabilization by mutations of frontotemporal dementia and parkinsonism linked to chromosome 17
L. Varani, M. Hasegawa, M. G. Spillantini, M. J. Smith, J. R. Murrell, B. Ghetti, A. Klug, M. Goedert, G. Varani
in Proc Natl Acad Sci U S A (1999) vol. 96 pp8229-34
RNA-protein interactions and protein-protein interactions during regulation of eukaryotic gene expression
L. Varani, A. Ramos, P. Cole, D. Neuhaus, G. Varani
in J Korean Magnetic Resonance Soc (1998) vol. 2 pp152-157
Partially folded structure of monomeric bovine beta-lactoglobulin
H. Molinari, L. Ragona, L. Varani, G. Musco, R. Consonni, L. Zetta, H. L. Monaco
in FEBS Lett (1996) vol. 381 pp237-43