Abstract
The GTP-ase binding domain (GBD) of the signaling protein Wiskott-Aldrich Syndrome Protein (WASP) is intrinsically disordered and mutations in it have been linked with Wiskott-Aldrich Syndrome (WAS), an X-linked disorder characterized by thrombocytopenia, eczema and recurrent infections. Here, we use molecular dynamics simulations and the semi-empirical GROMOS 45A3 force field to study interaction of the GBD domain of WASP with a fragment of the protein EspF(U) as well as with the VCA domain of WASP (auto-inhibited state). EspF(U) is secreted and used by enterohaemorrhagic Escherichia colt to hijack eukaryotic cytoskeletal machinery, and it does so by competitively disrupting the auto-inhibitory interaction between GBD and VCA domains of WASP. In addition, naturally occurring mutations in the VCA domain cause different variants of WAS. Our simulations confirm that the EspF(U) domain binds the GBD domain similarly to the VCA domain, which explains why these two binding partners are competitive binders of the GBD domain. Furthermore, we propose a possible mechanism to explain the higher affinity of EspF(U) for the GBD domain. Finally, we show that the mutations in the VCA domain responsible for Wiskott-Aldrich syndrome can cause formation of beta-sheets in the VCA domain. This effect, combined with the mutation-induced rearrangement of the salt bridge network, consequently disables tight binding between GBD and VCA domains. Overall, our results provide a microscopic, dynamic picture behind the two main ways through which the interactions involving the GBD domain of WASP participate in different disease processes.
Original language | English |
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Pages (from-to) | 211-220 |
Number of pages | 10 |
Journal | Croatica Chemica Acta |
Volume | 84 |
Issue number | 2 |
DOIs | |
Publication status | Published - 2011 |
Austrian Fields of Science 2012
- 106041 Structural biology