Abstract
Src-homology regions 3 (SH3) domain is essential for the down-regulation of tyrosine kinase activity. Mutation A39V/N53P/V55L of SH3 is found to be relative to the urgent misfolding diseases. To gain insight, the human and gallus SH3 domains (PDB ID: 1NYG and 2LP5), including 58 amino acids in each protein, were selected for MD simulations (Amber11, ff99SB force field) and cluster analysis to investigate the influence of mutations on the spatial structure of the SH3 domain. It is found that the large conformational change of mutations mainly exists in three areas in the vicinity of protein core: RT loop, N-src loop, distal β-hairpin to 310 helix. The C-terminus of the mutated gallus SH3 is disordered after simulation, which represents the intermediate state of aggregation. The disappeared strong Hbond net in the mutated human and gallus systems will make these mutated proteins looser than the wild-type proteins. Additionally, by performing the REMD simulations on the gallus SH3 domain, the mutated domain is found to have an obvious effect on the unfolding process. These studies will be helpful for further aggregation mechanisms investigations on SH3 family.
Highlights
Amyloids are insoluble b sheet-rich fibrous protein aggregates sharing specific structural traits [1]
We focus on the folding and aggregation processes of the human and gallus Fyn Src-homology regions 3 (SH3) domains by using mutation studies, molecular dynamics (MD) simulations, and replica exchange molecular dynamics (REMD) method
In the case of human SH3 domain, it is easy to find that the backbone root mean square deviation (RMSD) values of both the hn and hm systems are stabilized at around 2.0 A (Figure 2A)
Summary
Amyloids are insoluble b sheet-rich fibrous protein aggregates sharing specific structural traits [1]. Some misfolded structures of amyloids, mainly caused by site- directed mutagenesis, alter their proper configuration such that they erroneously interact with one another or other cell components forming insoluble fibrils. These misfolded structures associate with the pathology of more than 20 serious human diseases, including Alzheimer’s and Parkinson’s disease and type II diabetes [2,3,4,5]. Mutations and deletions of the SH3 domains in protein tyrosine kinases will result in the activation of the transforming potential of these proteins This implies that SH3 domain plays an important role in the down-regulation of kinase activity either via the interactions with other regulatory proteins or via an intramolecular mechanism [13,14]. Mutations on some conserved residues of SH3 domain will influence the regular folding process, leading to protein misfolding diseases
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