Structural neurobiology
Human membrane proteins

Structural biology of human myelin membrane proteins

Myelin is a crucial structure for the normal functioning of the vertebrate nervous system. Here, we have used multiple state-of-the-art technologies at large international research infrastructures, enabling methods not available in Norway, to obtain 3D structural information on some of the most hydrophobic protein molecules in the human body, which are responsible for the correct structure and function of the myelin sheath in the human central nervous system. The results will provide new ways to address the structure of human myelin and its disorders.

myelin membrane proteins
An updated model for the central nervous system myelin sheath at the molecular level. Ruskamo et al. (2022) Cell. Mol. Life Sci. 79: 419.
Salla Ruskamo

Main content

Myelin is a specific supramolecular biostructure in the vertebrate nervous system, made of unique proteins and stacked lipid bilayers. The quantitatively major protein in human central nervous system myelin is the proteolipid protein (PLP) - also one of the most hydrophobic proteins in the human body. The latter makes this protein extremely challenging to study under laboratory conditions. We have over the past years succeeded in producing human PLP recombinantly in large scale by overexpression in cultured insect cells, and the samples have now been subjected to 3D structural studies using a variety of methods. 

Using, for example, synchrotron radiation circular dichroism spectroscopy, small-angle X-ray scattering, neutron scattering, X-ray diffraction, atomic force microscopy, and electron cryomicroscopy, we have shed light on the 3D structure of PLP and its smaller isoform DM-20. We observe tight protein-mediated junctions between lipid bilayers and build a model for human central nervous system compact myelin based on the current data and our earlier work. The results provide novel, high-resolution insights into the development of the myelinated nervous system at the molecular level, and they will be useful in the future for the understanding of disorders related to myelination. 

This research was a collaboration between us and scientists at several large international research infrastructures, including Biocenter Oulu (Finland), iNANO/Aarhus University (Denmark), Institut Laue-Langevin (ILL), Grenoble (France), Central European Institute of Technology, Masaryk University, Brno (Czech Republic), and the Australian Nuclear Science and Technology Organisation, Sydney (Australia). In addition, the European infrastructures at EMBL/DESY (Hamburg, Germany), ISA (Aarhus, Denmark), and SOLEIL (Paris, France) were crucial for the success of the project. 

All in all, this project has been a 10-year tour-de-force by our extremely talented, and sorely missed, colleague Dr. Salla Ruskamo at the University of Oulu (Finland). Now that she has moved on with her career, we wish to acknowledge her outstanding contributions to our research project as a whole and wish her all the best for the future. 

Reference: Ruskamo S., Raasakka A., Pedersen J.S., Martel A., Škubník K., Darwish T., Porcar L. & Kursula P. (2022) Human myelin proteolipid protein structure and lipid bilayer stacking. Cell. Mol. Life Sci. 79: 419.