Myelin membrane assembly is driven by a phase transition of myelin basic proteins into a cohesive protein meshwork

PLoS Biol. 2013;11(6):e1001577. doi: 10.1371/journal.pbio.1001577. Epub 2013 Jun 4.

Abstract

Rapid conduction of nerve impulses requires coating of axons by myelin. To function as an electrical insulator, myelin is generated as a tightly packed, lipid-rich multilayered membrane sheath. Knowledge about the mechanisms that govern myelin membrane biogenesis is required to understand myelin disassembly as it occurs in diseases such as multiple sclerosis. Here, we show that myelin basic protein drives myelin biogenesis using weak forces arising from its inherent capacity to phase separate. The association of myelin basic protein molecules to the inner leaflet of the membrane bilayer induces a phase transition into a cohesive mesh-like protein network. The formation of this protein network shares features with amyloid fibril formation. The process is driven by phenylalanine-mediated hydrophobic and amyloid-like interactions that provide the molecular basis for protein extrusion and myelin membrane zippering. These findings uncover a physicochemical mechanism of how a cytosolic protein regulates the morphology of a complex membrane architecture. These results provide a key mechanism in myelin membrane biogenesis with implications for disabling demyelinating diseases of the central nervous system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amyloid / metabolism
  • Animals
  • HEK293 Cells
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Membranes / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Mutant Proteins / chemistry
  • Mutant Proteins / metabolism
  • Myelin Basic Protein / chemistry
  • Myelin Basic Protein / metabolism*
  • Myelin Sheath / metabolism*
  • Phase Transition*
  • Protein Binding
  • Protein Structure, Quaternary
  • Protein Structure, Secondary
  • Protein Structure, Tertiary

Substances

  • Amyloid
  • Mutant Proteins
  • Myelin Basic Protein

Grant support

The work was supported by an ERC Starting Grant (M.S.) and grants from the German Research Foundation (SI 746/9-1; TRR43). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.