Oral Presentation 2014 International Biophysics Congress

Interactions of Dok7 with anionic lipid bilayers studied by multiscale MD simulation (#32)

Amanda Buyan 1 , Antreas C. Kalli 1 , Mark S.P. Sansom 1
  1. Biochemistry, University of Oxford, Oxford, UK

Signal transduction at the cell membrane is essential for many biological processes, such as mitosis, cell regeneration, and muscle contraction. In many cases, receptor tyrosine kinases (RTKs) form transient complexes   for cytosolic signalling and membrane recognition proteins. Downstream-of-Kinase 7 (Dok7) is a soluble cytosolic protein involved in the Muscle-Specific Kinase (MuSK) signalling pathway. Dok7 binds to MuSK to facilitate clustering of acetylcholine receptors.  Mutations in Dok7 have been known to result in varying degrees of severity of congenital myasthenic syndromes, which is characterised by impaired muscle contractions.  Dok7's pleckstrin-homology (PH) and phosphotyrosine-binding (PTB) domains have previously been structurally characterised, and though there is evidence to suggest how it interacts with MuSK, it is remains unknown how Dok7 interacts with the cytosolic face of mammalian cell membranes.

Here we apply a multi-scale Molecular Dynamics simulations approach to explore the interactions of Dok7 with model membranes of different lipid compositions.  Coarse-grained (CG) simulations are used to define the possible modes of attachment of Dok7 to a lipid bilayer, while atomistic simulations are used to refine the resultant interactions of the protein with specific lipids present in the bilayer.  These computational studies highlight the importance of understanding the interaction of cytosolic proteins with the cell membrane in the context of the broader question of mechanisms of signalling.