Rational Design of Mutations That Change the Aggregation Rate of a Protein While Maintaining Its Native Structure and Stability

Overview

Journal Sci Rep

Specialty Science

Date 2016 May 7

PMID 27150430

Citations 19

Authors

Carlo Camilloni

Benedetta Maria Sala

Pietro Sormanni

Riccardo Porcari

Alessandra Corazza

Matteo De Rosa

Stefano Zanini

Alberto Barbiroli

Gennaro Esposito

Martino Bolognesi

Vittorio Bellotti

Michele Vendruscolo

Stefano Ricagno

Affiliations

Soon will be listed here.

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.

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