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IS-AUR-Samarb.progr. Norge Frankrike

Molecular dissection of human peripheral neuropathy

Awarded: NOK 49,976

Project Manager:

Project Number:

294901

Application Type:

Project Period:

2019 - 2020

Location:

Subject Fields:

The correct functioning of the vertebrate nervous system requires the rapid conduction of nerve impulses over large distances. This saltatory conduction is enabled by the myelin sheath, a tighly packed, multilayered membrane wrapped around selected axons. Myelin is formed of dozens of lipid bilayers, containing specific integral and peripheral membrane proteins that stack lipid membranes into multilayers. Although many myelin proteins were, due to their high natural abundance, initially isolated >50 years ago, little is still known about their 3D structure or the molecular mechanisms of their function in myelin formation. Protein zero (P0) is the most abundant protein in peripheral nervous system (PNS) myelin, and this integral membrane protein is a target of dozens of CMT mutations. The extracellular domain is engaged in homophilic interactions, while the C-terminal cytoplasmic domain binds to membrane surfaces. A wide range of techniques will be used to study the folding and membrane interactions of the P0 cytoplasmic domain and its mutated variants; this application specifically targets NMR experiments to be done in collaboration with Dr. Robert Schneider at the University of Lille, France. Dr. Schneider is experienced in using NMR techniques to study membrane proteins, and his research interests include biomedically relevant flexible/disordered proteins and their complexes with lipid membranes. NMR spectroscopy will be used to study the structure, dynamics, and lipid interactions of the P0 cytoplasmic domain. The first test NMR spectrum of the P0 cytoplasmic domain has been recently measured, and the sample is definitely suitable for further structure/dynamics analyses. Work is ongoing to produce isotopically labelled disease variants of the cytoplasmic domain for more detailed studies, supported by this application.

Funding scheme:

IS-AUR-Samarb.progr. Norge Frankrike