title: Deciphering the role of the thermodynamic and kinetic stabilities of SH3 domains on their aggregation inside bacteria.
abstract: The formation of insoluble deposits by globular proteins underlies the onset of many human diseases. Recent studies suggest a relationship between the thermodynamic stability of proteins and their in vivo aggregation. However, it has been argued that, in the cell, the occurrence of irreversible aggregation might shift the system from equilibrium, in such a way that it could be the rate of unfolding and associated kinetic stability instead of the conformational stability that controls protein deposition. This is an important but difficult to decipher question, because kinetic and thermodynamic stabilities appear usually correlated. Here we address this issue by comparing the in vitro folding kinetics and stability features of a set of non-natural SH3 domains with their aggregation properties when expressed in bacteria. In addition, we compare the in vitro stability of the isolated domains with their effective stability in conditions that mimic the cytosolic environment. Overall, the data argue in favor of a thermodynamic rather than a kinetic control of the intracellular aggregation propensities of small globular proteins in which folding and unfolding velocities largely exceed aggregation rates. These results have implications regarding the evolution of proteins.
authors.affiliation: Institut de Biotecnologia i de Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra (Barcelona), Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Castillo
authors.forename: Alba
authors.initials: A
authors.lastname: Espargaró
authors.forename: Veronica
authors.initials: V
authors.lastname: Gordo
authors.forename: Josep
authors.initials: J
authors.lastname: Vendrell
authors.forename: Salvador
authors.initials: S
authors.lastname: Ventura
mesh_terms: D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D009154:Mutation; D017510:Protein Folding; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D058767:Protein Unfolding; D011994:Recombinant Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D012995:Solubility; D013816:Thermodynamics; D018909:src Homology Domains
chemical_list: D011994:Recombinant Proteins