A Size Barrier Limits Protein Diffusion at the Cell Surface to Generate Lipid-Rich Myelin-Membrane Sheets

Abstract

The insulating layers of myelin membrane wrapped around axons by oligodendrocytes are essential for the rapid conduction of nerve impulses in the central nervous system. To fulfill this function as an electrical insulator, myelin requires a unique lipid and protein composition. Here we show that oligodendrocytes employ a barrier that functions as a physical filter to generate the lipid-rich myelin-membrane sheets. Myelin basic protein (MBP) forms this molecular sieve and restricts the diffusion of proteins with large cytoplasmic domains into myelin. The barrier is generated from MBP molecules that line the entire sheet and is, thus, intimately intertwined with the biogenesis of the polarized cell surface. This system might have evolved in oligodendrocytes in order to generate an anisotropic membrane organization that facilitates the assembly of highly insulating lipid-rich membranes.

Classic 18.5- and 21.5-kDa Myelin Basic Protein Isoforms Associate with Cytoskeletal and SH3-Domain Proteins in the Immortalized N19-Oligodendroglial Cell Line Stimulated by Phorbol Ester and IGF-1

“…The CNS myelin, although mostly composed of lipids, possesses many fundamental proteins which are essential for proper structural and functional integrity of the sheath (reviewed by [7]). Among these essential proteins are the myelin basic proteins (MBPs) [8][9][10][11][12][13], a family composed of developmentally regulated members arising from different transcription start sites of the Golli (Gene of Oligodendrocyte Lineage) complex, with further alternatively-spliced isoforms and combinatorial post-translational modifications [14]. 'Classic' MBP isoforms arise from transcription start site 3 and range in size from 14 kDa to the full-length 21.5-kDa transcript.…”

The myelin membrane-associated enzyme 2′,3′-cyclic nucleotide 3′-phosphodiesterase: on a highway to structure and function

“…Myelin contains a set of unique proteins that generally display strict localization to either compact or non-compact myelin, which is thought to be at least partially driven by size exclusion [3,4] . The myelin environment being low in aqueous content and harboring negatively charged, tightly packed membrane interfaces, myelin proteins typically exhibit attributes such as strong hydrophobicity, peripheral membrane association, transmembrane domains, and a high positive net charge, as well as intrinsic disorder [5] .…”

“…The membrane sheets of myelin are densely packed, resulting in the extrusion of cytosolic elements and in the formation of a lipid-rich, insulating sheath that enables the acceleration of nerve impulses. A mature myelin sheath can be morphologically divided into compact and non-compact myelin, of which the latter has a higher cytosolic content and further contains several subcompartments, such as the abaxonal and adaxonal layers, as well as the paranodal loops [1,2] .Myelin contains a set of unique proteins that generally display strict localization to either compact or non-compact myelin, which is thought to be at least partially driven by size exclusion [3,4] . The myelin environment being low in aqueous content and harboring negatively charged, tightly packed membrane interfaces, myelin proteins typically exhibit attributes such as strong hydrophobicity, peripheral membrane association, transmembrane domains, and a high positive net charge, as well as intrinsic disorder [5] .…”

The 21.5-kDa isoform of myelin basic protein has a non-traditional PY-nuclear-localization signal

“…The 18.5-kDa isoform predominates in adult human myelin and has been the most studied. Its main purpose is adhesion of the cytoplasmic leaflets of OLG membranes [8] to form a "molecular sieve" [10,11]. However, this protein is multifunctional and interacts with numerous other proteins including actin, tubulin, Ca 2+ -activated calmodulin, and SH3-domain proteins (reviewed in [12][13][14][15][16][17][18][19]).…”