Max Planck Institute of Experimental Medicine, Göttingen, Germany.
PLoS Biol. 2013;11(6):e1001577. doi: 10.1371/journal.pbio.1001577. Epub 2013 Jun 4.
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.
神经冲动的快速传导需要轴突被髓鞘包裹。为了作为电绝缘体发挥作用，髓鞘生成作为一个紧密堆积的、富含脂质的多层膜鞘。为了理解髓鞘在多发性硬化等疾病中解体的机制，需要了解控制髓鞘膜生物发生的机制。在这里，我们表明，髓鞘碱性蛋白利用其内在的相分离能力产生的弱力来驱动髓鞘的生物发生。髓鞘碱性蛋白分子与膜双层的内叶结合诱导进入凝聚的网格状蛋白网络的相转变。这种蛋白质网络的形成与淀粉样纤维形成具有相似的特征。该过程由苯丙氨酸介导的疏水性和类淀粉样相互作用驱动，为蛋白质挤出和髓鞘膜拉链提供了分子基础。这些发现揭示了一种胞质蛋白如何调节复杂膜结构形态的物理化学机制。这些结果为中枢神经系统脱髓鞘疾病提供了一种关键的髓鞘膜生物发生机制。
