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. [10.1038/srep25559]

Rational design of mutations that change the aggregation rate of a protein while maintaining its native structure and stability

C. Camilloni;B.M. Sala
Secondo
;
M. De Rosa;A. Barbiroli;M. Bolognesi;S. Ricagno
Ultimo
2016

Abstract

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.
replica-averaged metadynamics; amyloid formation; beta(2)-microglobulin; beta-2-microglobulin; state; NMR; association; edge; competition; solubility
Settore BIO/10 - Biochimica
Settore FIS/07 - Fisica Applicata(Beni Culturali, Ambientali, Biol.e Medicin)
   From basic knowledge on the dynamics of b2-m self aggregation to the discovery of new inhibitors of amyloidogenesis
   MINISTERO DELL'ISTRUZIONE E DEL MERITO
   RBFR109EOS_002
6-mag-2016
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/384012
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