A single mutation in an SH3 domain increases amyloid aggregation by accelerating nucleation, but not by destabilizing thermodynamically the native state.


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. Study holds ProTherm entries: 24940, 24941, 24942, 24943, 24944, 24945, 24946, 24947, 24948, 24949, 24950, 24951, 24952, 24953, 24954 Extra Details: Amyloid; Thermodynamics; Protein stability; Differential scanning calorimetry Dynamic light scattering

Submission Details

ID: 7kVZoDD74

Submitter: Connie Wang

Submission Date: April 24, 2018, 8:55 p.m.

Version: 1

Publication Details
Varela L;Morel B;Azuaga AI;Conejero-Lara F,FEBS Lett. (2009) A single mutation in an SH3 domain increases amyloid aggregation by accelerating nucleation, but not by destabilizing thermodynamically the native state. PMID:19183554
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