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Publication: Solution NMR structure and molecular dynamics simulations of murine 18.5-kDa myelin basic protein segment (S72-S107) in association with dodecylphosphocholine micelles

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Title Solution NMR structure and molecular dynamics simulations of murine 18.5-kDa myelin basic protein segment (S72-S107) in association with dodecylphosphocholine micelles
Authors/Editors* Mumdooh A.M Ahmed, Miguel De Avila, Eugenia Polverini, Kyrylo Bessonov, Vladimir V. Bamm, George Harauz
Where published* Biochemistry
How published* Journal
Year* 2012
Volume
Number
Pages
Publisher ACS - Americsn Chemical Society
Keywords myelin basic protein, myelin membrane, intrinsically-disordered proteins, amphipathic α-helix, poly-proline type II conformation, SH3-domain, NMR spectroscopy, dodecylphosphocholine micelles, molecular dynamics
Link http://dx.doi.org/10.1021/bi300998x
Abstract
The 18.5-kDa myelin basic protein (MBP), the most abundant splice isoform in adult mammalian myelin, is a multifunctional, intrinsically-disordered protein involved in the development and compaction of the myelin sheath in the central nervous system. A highly-conserved central segment comprises a membrane-anchoring amphipathic α-helix followed by a proline-rich segment that represents a ligand for SH3-domain-containing proteins. Here, we have determined using solution NMR spectroscopy the structure of a 36-residue peptide fragment of MBP (murine 18.5-kDa residues S72-S107, denoted the α2-peptide) comprising these two structural motifs, in association with dodecylphosphocholine (DPC) micelles. The structure was calculated using CS-ROSETTA (version 1.01) because the NOE restraints were insufficient for this protein. The experimental studies were complemented by molecular dynamics simulations of a corresponding 24-residue peptide fragment (murine 18.5-kDa residues E80-G103, denoted the MD-peptide), also in association with a DPC micelle in silico. The experimental and theoretical results agreed well with one another, despite the independence of the starting structures and analyses, both showing membrane-association via the amphipathic α-helix, and a sharp bend in the vicinity of the Pro93 residue (murine 18.5-kDa sequence numbering). Overall, the conformations elucidated here show how the SH3-ligand is presented to the cytoplasm for interaction with SH3-domain-containing proteins such as Fyn, and contribute to our understanding of myelin architecture at the molecular level.
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