研究领域

Biological/Theoretical

In the last 15 years our research has been focused on the development of methods of characterising the structure, dynamics and interactions of proteins in previously inaccessible states. These methods are based on the use of experimental data, in particular from nuclear magnetic resonance spectroscopy, as structural restraints in molecular dynamics simulations. Through this approach it is possible to obtain information about a variety of protein conformations, as for example those populated during the folding process, and about protein interactions in complex environments, including those generating aggregate species that are associated with neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. More recently, these studies have led us to investigate the physico-chemical principles of proteins homeostasis and their application to the development of therapeutic strategies against neurodegenerative diseases. Starting from the observation that proteins are expressed in the cell at levels close to their solubility limits, we are developing approaches to prevent or delay misfolding disorders based on the enhancement of our quality control mechanisms against protein aggregation.

近期论文

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The s2D method: Simultaneous sequence-based prediction of the statistical populations of ordered and disordered regions in proteins. P Sormanni, C Camilloni, P Fariselli, M Vendruscolo – Journal of Molecular Biology (2015) 427, 982 (DOI: 10.1016/j.jmb.2014.12.007) A molecular chaperone breaks the catalytic cycle that generates toxic Aβ oligomers. SI Cohen, P Arosio, J Presto, FR Kurudenkandy, H Biverstål, L Dolfe, C Dunning, X Yang, B Frohm, M Vendruscolo, J Johansson, CM Dobson, A Fisahn, TP Knowles, S Linse – Nature Structural & Molecular Biology (2015) 22, 207 (DOI: 10.1038/nsmb.2971) Lipid vesicles trigger α-synuclein aggregation by stimulating primary nucleation. C Galvagnion, AK Buell, G Meisl, TC Michaels, M Vendruscolo, TP Knowles, CM Dobson – Nature Chemical Biology (2015) 11, 229 (DOI: 10.1038/nchembio.1750) The CamSol method of rational design of protein mutants with enhanced solubility. P Sormanni, FA Aprile, M Vendruscolo – Journal of Molecular Biology (2015) 427, 478 (DOI: 10.1016/j.jmb.2014.09.026) Supersaturation is a major driving force for protein aggregation in neurodegenerative diseases. P Ciryam, R Kundra, RI Morimoto, CM Dobson, M Vendruscolo – Trends Pharmacol Sci (2015) 36, 72 (DOI: 10.1016/j.tips.2014.12.004) Structure of a low-population intermediate state in the release of an enzyme product. A De Simone, FA Aprile, A Dhulesia, CM Dobson, M Vendruscolo – eLife (2015) 4 (DOI: 10.7554/eLife.02777) Supersaturation is a major driving force for protein aggregation in neurodegenerative diseases. P Ciryam, R Kundra, RI Morimoto, CM Dobson, M Vendruscolo – Trends in Pharmacological Sciences (2015) 36, 72 (DOI: 10.1016/j.tips.2014.12.004) The s2D Method: Simultaneous Sequence-Based Prediction of the Statistical Populations of Ordered and Disordered Regions in Proteins. P Sormanni, C Camilloni, P Fariselli, M Vendruscolo – Journal of molecular biology (2014) 427, 982 (DOI: 10.1016/j.jmb.2014.12.007) Characterization of the Conformational Fluctuations in the Josephin Domain of Ataxin-3. D Sanfelice, A De Simone, A Cavalli, S Faggiano, M Vendruscolo, A Pastore – Biophys J (2014) 107, 2932 (DOI: 10.1016/j.bpj.2014.10.008) The H50Q Mutation Induces a 10-fold Decrease in the Solubility of α-Synuclein R Porcari, C Proukakis, CA Waudby, B Bolognesi, PP Mangione, JF Paton, S Mullin, LD Cabrita, A Penco, A Relini, G Verona, M Vendruscolo, M Stoppini, GG Tartaglia, C Camilloni, J Christodoulou, AH Schapira, V Bellotti – J Biol Chem (2015) 290, 2395 (DOI: 10.1074/jbc.m114.610527) Erratum to ADP ribosylation adapts an ER chaperone response to short-term fluctuations in unfolded protein load [198 3 (2012) 371-385] doi 10.1083/jcb.20120200511112014c JE Chambers, K Petrova, G Tomba, M Vendruscolo, D Ron – The Journal of cell biology (2014) 207, 569 (DOI: 10.1083/jcb.20120200511112014c) A Relationship between the Transient Structure in the Monomeric State and the Aggregation Propensities of α-Synuclein and β-Synuclein. JR Allison, RC Rivers, JC Christodoulou, M Vendruscolo, CM Dobson – Biochemistry (2014) 53, 7170 (DOI: 10.1021/bi5009326) Understanding the frustration arising from the competition between function, misfolding, and aggregation in a globular protein. S Gianni, C Camilloni, R Giri, A Toto, D Bonetti, A Morrone, P Sormanni, M Brunori, M Vendruscolo – Proceedings of the National Academy of Sciences of the United States of America (2014) 111, 14141 (DOI: 10.1073/pnas.1405233111) Identification and characterization of PKCγ, a kinase associated with SCA14, as an amyloidogenic protein. H Takahashi, N Adachi, T Shirafuji, S Danno, T Ueyama, M Vendruscolo, AN Shuvaev, T Sugimoto, T Seki, D Hamada, K Irie, H Hirai, N Sakai, N Saito – Hum Mol Genet (2015) 24, 525 (DOI: 10.1093/hmg/ddu472) Equilibrium simulations of proteins using molecular fragment replacement and NMR chemical shifts. W Boomsma, P Tian, J Frellsen, J Ferkinghoff-Borg, T Hamelryck, K Lindorff-Larsen, M Vendruscolo – Proceedings of the National Academy of Sciences of the United States of America (2014) 111, 13852 (DOI: 10.1073/pnas.1404948111) NMR characterization of the conformational fluctuations of the human lymphocyte function-associated antigen-1 I-domain. HT Leung, P Kukic, C Camilloni, F Bemporad, A De Simone, FA Aprile, JR Kumita, M Vendruscolo – Protein Science (2014) 23, 1596 (DOI: 10.1002/pro.2538) Cyclophilin A catalyzes proline isomerization by an electrostatic handle mechanism. C Camilloni, AB Sahakyan, MJ Holliday, NG Isern, F Zhang, EZ Eisenmesser, M Vendruscolo – Proceedings of the National Academy of Sciences of the United States of America (2014) 111, 10203 (DOI: 10.1073/pnas.1404220111) Statistical mechanics of the denatured state of a protein using replica-averaged metadynamics. C Camilloni, M Vendruscolo – Journal of the American Chemical Society (2014) 136, 8982 (DOI: 10.1021/ja5027584) The CamSol method of rational design of protein mutants with enhanced solubility. P Sormanni, FA Aprile, M Vendruscolo – Journal of molecular biology (2014) 427, 478 (DOI: 10.1016/j.jmb.2014.09.026) The amyloid state and its association with protein misfolding diseases. TP Knowles, M Vendruscolo, CM Dobson – Nature Reviews Molecular Cell Biology (2014) 15, 384 (DOI: 10.1038/nrm3810)