title: Rational design of mutations that change the aggregation rate of a protein while maintaining its native structure and stability.
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.
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.|Department of Chemistry and Institute for Advanced Study, Technische Universität München, Lichtenbergstraße 4, D-85748 Garching, Germany.
authors.forename: Carlo
authors.initials: C
authors.lastname: Camilloni
authors.affiliation: Dipartimento di Bioscienze, Università degli Studi di Milano, 20133 Milano, Italy.
authors.forename: Benedetta Maria
authors.initials: BM
authors.lastname: Sala
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Pietro
authors.initials: P
authors.lastname: Sormanni
authors.affiliation: Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, University College London, London NW3 2PF, UK.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Porcari
authors.affiliation: Dipartimento di Scienze Mediche e Biologiche, Università di Udine, 33100 Udine, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Corazza
authors.affiliation: Dipartimento di Bioscienze, Università degli Studi di Milano, 20133 Milano, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: De Rosa
authors.affiliation: Dipartimento di Scienze Mediche e Biologiche, Università di Udine, 33100 Udine, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Zanini
authors.affiliation: Dipartimento di Scienze per gli Alimenti, la Nutrizione e l'Ambiente, Università degli Studi di Milano, 20133 Milano, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Barbiroli
authors.affiliation: Dipartimento di Scienze Mediche e Biologiche, Università di Udine, 33100 Udine, Italy.|Science and Math Division, New York University Abu Dhabi, Saadiyat Island, Abu Dhabi, UAE.
authors.forename: Gennaro
authors.initials: G
authors.lastname: Esposito
authors.affiliation: Dipartimento di Bioscienze, Università degli Studi di Milano, 20133 Milano, Italy.|CIMAINA and CNR Istituto di Biofisica, c/o Dipartimento di Bioscienze, Università degli Studi di Milano, 20133 Milano, Italy.
authors.forename: Martino
authors.initials: M
authors.lastname: Bolognesi
authors.affiliation: Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, University College London, London NW3 2PF, UK.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Bellotti
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Michele
authors.initials: M
authors.lastname: Vendruscolo
authors.affiliation: Dipartimento di Bioscienze, Università degli Studi di Milano, 20133 Milano, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Ricagno
mesh_terms: D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D056004:Molecular Dynamics Simulation; D050505:Mutant Proteins / Q000737:chemistry; D009154:Mutation / Q000235:genetics*; D066329:Protein Aggregates / Q000235:genetics*; D055550:Protein Stability; D017433:Protein Structure, Secondary; D020539:Sequence Analysis, Protein; D013816:Thermodynamics; D001613:beta 2-Microglobulin / Q000737:chemistry* / Q000235:genetics*
chemical_list: D050505:Mutant Proteins; D066329:Protein Aggregates; D001613:beta 2-Microglobulin