Myelin Membrane Assembly Is Driven by a Phase Transition of Myelin Basic Proteins Into a Cohesive Protein Meshwork

Shweta Aggarwal,Mikael Simons,Steffen Frey,Nicolas Snaidero,Markus Zweckstetter,Andreas Janshoff,Anja Schneider,Iwan A T Schaap,Marie-Theres Weil,Paula Sánchez,Dirk Görlich,Gesa Pähler

doi:10.1371/journal.pbio.1001577

Abstract

Author SummaryMyelin is a specialized membrane that covers axons and serves as an insulator to enable the fast conduction of the action potentials. The importance of myelin membrane is highlighted in demyelinating diseases such as multiple sclerosis, which lead to severe neurological disability. Here, we describe a physicochemical mechanism of how myelin is generated and assembled. We find that myelin basic protein (MBP) molecules undergo a phase transition into a cohesive meshwork at the membrane interface, which drives structural changes in the membranes. We provide evidence that the interaction of myelin basic proteins with the inner leaflet of the myelin bilayer results in charge neutralization and triggers self-association of the protein into larger polymers. Interactions between MBP molecules are mediated by hydrophobic phenylalanine residues and amyloid-like association. We propose that phase transition of MBP from a cytoplasmic soluble pool into a cohesive functional amyloid-like assembly is one of the key mechanisms in myelin membrane biogenesis.

Highlights

Compartmentalization and spatial organization of molecules is essential to establish functionally specialized domains within a cell
The importance of myelin membrane is highlighted in demyelinating diseases such as multiple sclerosis, which lead to severe neurological disability
We find that myelin basic protein (MBP) molecules undergo a phase transition into a cohesive meshwork at the membrane interface, which drives structural changes in the membranes

Summary

Introduction

Compartmentalization and spatial organization of molecules is essential to establish functionally specialized domains within a cell. Segregation of molecules can occur over several length scales ranging from the formation of complexes of few interacting molecules to the generation of micrometer-sized domains. Whereas structural biology has provided us with a wealth of knowledge of how specific molecular interactions occur within macromolecular complexes, little is known about the rules that drive segregation of molecules into large collectives. Phase separations, which constitute a well-recognized phenomenon in nonbiological system, are emerging as a powerful mechanism of how cells organize molecules over larger length scales [1,2]. Less is known about how phase separations structure lipid membranes. We addressed this issue using myelin as a model membrane. One essential function of MBP is to bring the opposing cytoplasmic surfaces of the myelin membrane closely together [16].

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