Modulation of the internal dynamics of the Homer1 EVH1 domain by putative autism-associated mutations

The EVH1 domain of the Homer1 scaffold protein interacts with the proline-rich region of Shank3, forming a key network within the postsynaptic density. Two mutations in EVH1, M65I and S97L, were suggested to be associated with autism spectrum disorder. Combining experimental and computational investigations, we show here that neither the overall structure nor the partner binding properties of the mutants exhibit substantial changes relative to the wild type. Compared to the S97L variant, the M65I mutant exhibits larger chemical shift perturbations both upon the mutation itself and during partner binding, and also shows signs of thermal destabilization. Integration of computational and NMR investigations suggests that both mutations perturb the s-ms time scale internal motions of the EVH1 domain.