Molecular Dynamics of the Association of L-Selectin and FERM Regulated by PIP2 |
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Authors: | Fude Sun Carsten FE Schroer Lida Xu Huiwei Yin Siewert J Marrink Shi-Zhong Luo |
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Institution: | 1. Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China;2. Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, the Netherlands |
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Abstract: | Phosphatidylinositol 4,5-bisphosphate (PIP2) acts as a signaling lipid, mediating membrane trafficking and recruitment of proteins to membranes. A key example is the PIP2-dependent regulation of the adhesion of L-selectin to the cytoskeleton adaptors of the N-terminal subdomain of ezrin-radixin-moesin (FERM). The molecular details of the mediating behavior of multivalent anionic PIP2 lipids in this process, however, remain unclear. Here, we use coarse-grained molecular dynamics simulation to explore the mechanistic details of PIP2 in the transformation, translocation, and association of the FERM/L-selectin complex. We compare membranes of different compositions and find that anionic phospholipids are necessary for both FERM and the cytoplasmic domain of L-selectin to absorb on the membrane surface. The subsequent formation of the FERM/L-selectin complex is strongly favored by the presence of PIP2, which clusters around both proteins and triggers a conformational transition in the cytoplasmic domain of L-selectin. We are able to quantify the effect of PIP2 on the association free energy of the complex by means of a potential of mean force. We conclude that PIP2 behaves as an adhesive agent to enhance the stability of the FERM/L-selectin complex and identify key residues involved. The molecular information revealed in this study highlights the specific role of membrane lipids such as PIP2 in protein translocation and potential signaling. |
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Keywords: | Corresponding author |
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