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A single mutation in an SH3 domain increases amyloid aggregation by accelerating nucleation, but not by destabilizing thermodynamically the native state
Author(s) -
Varela Lorena,
Morel Bertrand,
Azuaga Ana I.,
Conejero-Lara Francisco
Publication year - 2009
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2009.01.033
Subject(s) - mutant , biophysics , fibril , chemistry , amyloid (mycology) , nucleation , sh3 domain , mutation , kinetics , fibrillation , crystallography , biochemistry , biology , receptor , proto oncogene tyrosine protein kinase src , physics , medicine , inorganic chemistry , organic chemistry , quantum mechanics , gene , atrial fibrillation
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.