title: Myelin membrane assembly is driven by a phase transition of myelin basic proteins into a cohesive protein meshwork.
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.
authors.affiliation: Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Shweta
authors.initials: S
authors.lastname: Aggarwal
authors.forename: Nicolas
authors.initials: N
authors.lastname: Snaidero
authors.forename: Gesa
authors.initials: G
authors.lastname: Pähler
authors.forename: Steffen
authors.initials: S
authors.lastname: Frey
authors.forename: Paula
authors.initials: P
authors.lastname: Sánchez
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
authors.forename: Andreas
authors.initials: A
authors.lastname: Janshoff
authors.forename: Anja
authors.initials: A
authors.lastname: Schneider
authors.forename: Marie-Theres
authors.initials: MT
authors.lastname: Weil
authors.forename: Iwan A T
authors.initials: IA
authors.lastname: Schaap
authors.forename: Dirk
authors.initials: D
authors.lastname: Görlich
authors.forename: Mikael
authors.initials: M
authors.lastname: Simons
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000378:metabolism; D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008566:Membranes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D004676:Myelin Basic Protein / Q000737:chemistry / Q000378:metabolism*; D009186:Myelin Sheath / Q000378:metabolism*; D044367:Phase Transition; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D000682:Amyloid; D050505:Mutant Proteins; D004676:Myelin Basic Protein