A single mutation in an SH3 domain increases amyloid aggregation by accelerating nucleation, but not by destabilizing thermodynamically the native state |
| |
Authors: | Lorena Varela |
| |
Institution: | Departamento de Química Física e Instituto de Biotecnología, Facultad de Ciencias, Universidad de Granada, Campus Fuentenueva, 18071 Granada, Spain |
| |
Abstract: | We investigated the relationship between thermodynamic stability and amyloid aggregation propensity for a set of single mutants of the alpha-spectrin SH3 domain (Spc-SH3). Whilst mutations destabilizing the domain at position 56 did not enhance fibrillation, the N47A mutation increased the rate of amyloid fibril formation by 10-fold. Even under conditions of identical thermodynamic stability, the aggregation rate was much higher for the N47A mutant than for the WT domain. We conclude that the N47A mutation does not change the apparent mechanism of fibrillation or the morphology of the amyloid fibrils, and that its amyloidogenic property is due to its effect upon the rate of the conformational events leading to nucleation and not to its overall destabilizing effect. |
| |
Keywords: | Spc-SH3 Src-homology 3 domain of α-spectrin DSC differential scanning calorimetry ThT thioflavin T DLS dynamic light scattering TEM transmission electron microscopy |
本文献已被 ScienceDirect 等数据库收录! |
|