Elucidating Phospholipid Membrane Binding of DEP domain in the Wnt Signaling Pathway

Francesco L Falginella^1,2, Robert Vácha^1,2,3

¹CEITEC – Central European Institute of Technology, Masaryk University, 625 00, Brno, Kamenice 753/5

²National Centre for Biomolecular Research, Masaryk University, 625 00, Brno, Kamenice 5

³Department of Condensed Matter Physics, Masaryk University, 611 37, Brno, Kotlářská 267/2

falginella.francesco@gmail.com

Signal transduction represents the mechanism by which cells communicate and interact with the extracellular environment and each other. Wnt signaling pathway is arguably one of the most studied and dissected pathway, due to its high level of conservation among species and involvement in a variety of (patho-)physiological processes [1]. Yet, the molecular events underlying the pathway activation and progression remain mostly elusive. It has been suggested that Dishevelled protein (DVL) plays the key role of a signaling hub for both canonical and non-canonical Wnt signaling branches [2,3]. In particular, a single DVL domain, called DEP (DVL, Egl-10, Pleckstrin), was shown to interact with phospholipid bilayers [4] and Wnt transmembrane receptor, Frizzled [5], triggering DVL recruitment to the plasma membrane (PM) and cytoplasmic signaling activation. By means of all-atom Molecular Dynamics simulations, we elucidated the structural details responsible for DEP-PM interaction and how this event is modulated by membrane lipid composition and the domain post-translational modifications (PTMs). Our results suggest that the recently identified phosphorylation sites on DEP domain [6] do not act as simple electrostatic modulators but rather make the interaction environment dependent.

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