Myelin Basic Protein (MBP) is a multifunctional protein involved in maintaining the stability and integrity of the myelin sheath by a variety of interactions with membranes, and with cytoskeletal and other proteins. In this chapter the interactions of MBP with two signalling proteins, the calmodulin (CaM) and an SH3-domain containing protein, and their modulation by post-translational modifications (PTMs) were investigated at an atomic level by means of the docking simulation approach, to gain further structural insight on the putative signalling role of MBP. Based on previously obtained experimental results, three CaM and one SH3-domain putative targets were identified in the classic 18.5 kDa MBP isoform and their interaction with the binding site of the receptor was modelled. The ability of CaM and of the SH3-domain to bind the MBP peptides was confirmed and the strength of the interaction seems to be of the same order of magnitude. The docking results on CaM highlight the conformational adaptability of MBP. The target peptides can adopt different binding modes, adapting the orientations of their side chains in such a way that the basic residues interact with the negatively-charged clusters at the extremities of the CaM binding tunnel and the hydrophobic ones anchor the MBP segments to its hydrophobic pockets. Thus it seems that CaM induces the binding mode that is most favourable for it, promoting the -helical conformation of its targets. On the contrary, the polyproline type II helical conformation that is a characteristic of SH3-domain ligands is already present on the MBP target in vitro under physiological conditions. The MBP - SH3-domain interaction occurs by means of salt bridges and cation-π interactions between the basic residues in the peptide and the negatively-charged and aromatic residues in the receptor, but the molecular recognition and association seems to be mediated by weak CH∙∙∙ interactions of the ligand prolyl residues with the aromatic residues in the binding site. The effects of PTMs on MBP peptides show a lowering of the CaM-MBP affinity after deimination, while phosphorylation seems to have only a minor effect. Phosphorylation or methylation of the MBP ligand did not cause any major inhibition of binding with the SH3-domain, beyond a somewhat less favourable interaction for phosphorylated peptides. Although the conformation of the MBP peptide in the SH3-domain pocket changed significantly, new interactions were able to substitute for those lost, in order to stabilize the complex.

Molecular Modelling of the Interaction of Myelin Basic Protein (MBP) Peptides with Signalling Proteins and Effects of Post-Translational Modifications / Polverini, Eugenia. - (2009), pp. 167-194.

Molecular Modelling of the Interaction of Myelin Basic Protein (MBP) Peptides with Signalling Proteins and Effects of Post-Translational Modifications

POLVERINI, Eugenia
2009-01-01

Abstract

Myelin Basic Protein (MBP) is a multifunctional protein involved in maintaining the stability and integrity of the myelin sheath by a variety of interactions with membranes, and with cytoskeletal and other proteins. In this chapter the interactions of MBP with two signalling proteins, the calmodulin (CaM) and an SH3-domain containing protein, and their modulation by post-translational modifications (PTMs) were investigated at an atomic level by means of the docking simulation approach, to gain further structural insight on the putative signalling role of MBP. Based on previously obtained experimental results, three CaM and one SH3-domain putative targets were identified in the classic 18.5 kDa MBP isoform and their interaction with the binding site of the receptor was modelled. The ability of CaM and of the SH3-domain to bind the MBP peptides was confirmed and the strength of the interaction seems to be of the same order of magnitude. The docking results on CaM highlight the conformational adaptability of MBP. The target peptides can adopt different binding modes, adapting the orientations of their side chains in such a way that the basic residues interact with the negatively-charged clusters at the extremities of the CaM binding tunnel and the hydrophobic ones anchor the MBP segments to its hydrophobic pockets. Thus it seems that CaM induces the binding mode that is most favourable for it, promoting the -helical conformation of its targets. On the contrary, the polyproline type II helical conformation that is a characteristic of SH3-domain ligands is already present on the MBP target in vitro under physiological conditions. The MBP - SH3-domain interaction occurs by means of salt bridges and cation-π interactions between the basic residues in the peptide and the negatively-charged and aromatic residues in the receptor, but the molecular recognition and association seems to be mediated by weak CH∙∙∙ interactions of the ligand prolyl residues with the aromatic residues in the binding site. The effects of PTMs on MBP peptides show a lowering of the CaM-MBP affinity after deimination, while phosphorylation seems to have only a minor effect. Phosphorylation or methylation of the MBP ligand did not cause any major inhibition of binding with the SH3-domain, beyond a somewhat less favourable interaction for phosphorylated peptides. Although the conformation of the MBP peptide in the SH3-domain pocket changed significantly, new interactions were able to substitute for those lost, in order to stabilize the complex.
2009
9781604566994
Molecular Modelling of the Interaction of Myelin Basic Protein (MBP) Peptides with Signalling Proteins and Effects of Post-Translational Modifications / Polverini, Eugenia. - (2009), pp. 167-194.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/1800935
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