A wide range of human diseases is associated with mutations that, destabilizing proteins native state, promote their aggregation. However, the mechanisms leading from folded to aggregated states are still incompletely understood. To investigate these mechanisms, we used a combination of NMR spectroscopy and molecular dynamics simulations to compare the native state dynamics of Beta-2 microglobulin (β2m), whose aggregation is associated with dialysis-related amyloidosis, and its aggregation-resistant mutant W60G. Our results indicate that W60G low aggregation propensity can be explained, beyond its higher stability, by an increased average protection of the aggregation-prone residues at its surface. To validate these findings, we designed β2m variants that alter the aggregation- prone exposed surface of wild-type and W60G β2m modifying their aggregation propensity. These results allowed us to pinpoint the role of dynamics in β2m aggregation and to provide a new strategy to tune protein aggregation by modulating the exposure of aggregation-prone residues.
Rational design of mutations that change the aggregation rate of a protein while maintaining its native structure and stability / C. Camilloni, B.M. Sala, P. Sormanni, R. Porcari, A. Corazza, M. De Rosa, S. Zanini, A. Barbiroli, G. Esposito, M. Bolognesi, V. Bellotti, M. Vendruscolo, S. Ricagno. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 6(2016 May 06), pp. 25559.1-25559.11.
|Titolo:||Rational design of mutations that change the aggregation rate of a protein while maintaining its native structure and stability|
SALA, BENEDETTA MARIA (Secondo)
RICAGNO, STEFANO (Ultimo)
|Parole Chiave:||replica-averaged metadynamics; amyloid formation; beta(2)-microglobulin; beta-2-microglobulin; state; NMR; association; edge; competition; solubility|
|Settore Scientifico Disciplinare:||Settore BIO/10 - Biochimica|
Settore FIS/07 - Fisica Applicata(Beni Culturali, Ambientali, Biol.e Medicin)
|Progetto:||From basic knowledge on the dynamics of b2-m self aggregation to the discovery of new inhibitors of amyloidogenesis|
|Data di pubblicazione:||6-mag-2016|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1038/srep25559|
|Appare nelle tipologie:||01 - Articolo su periodico|