Original scientific paper

https://doi.org/10.5562/cca1806

Computational Analysis of Binding of the GBD Domain of WASP to Different Binding Partners

Maria K Janowska ; Department of Biochemistry, Biophysics and Biotechnology, Jagiellonian University,30-387 Krakow, Poland; Department of Chemistry & Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA; Mediterranean Institute for Life Sciences, Split, HR-21000,
Ruben Zubac ; Mediterranean Institute for Life Sciences, Split, HR-21000, Croatia; Department of Physics, University of Split, Split, HR-21000, Croatia; Department of Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, Campus Vienna
Bojan Zagrovic ; Mediterranean Institute for Life Sciences, Split, HR-21000, Croatia; Department of Physics, University of Split, Split, HR-21000, Croatia; Department of Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, Campus Vienna

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 EspFU as well as with the VCA domain
of WASP (auto-inhibited state). EspFU is secreted and used by enterohaemorrhagic Escherichia coli
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 EspFU 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 EspFU for the GBD domain. Finally, we show that the mutations in the VCA domain responsible
for Wiskott-Aldrich syndrome can cause formation of β-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.(doi: 10.5562/cca1806)

Keywords

Wiskott-Aldrich syndrome protein; GBD domain; VCA domain; EspFU; molecular dynamics; GROMOS 45A3 force field

Hrčak ID:

71984

URI

https://hrcak.srce.hr/71984

Publication date:

3.10.2011.

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