Flexible Players within the Sheaths: The Intrinsically Disordered Proteins of Myelin in Health and Disease

Abstract

Myelin ensheathes selected axonal segments within the nervous system, resulting primarily in nerve impulse acceleration, as well as mechanical and trophic support for neurons. In the central and peripheral nervous systems, various proteins that contribute to the formation and stability of myelin are present, which also harbour pathophysiological roles in myelin disease. Many myelin proteins share common attributes, including small size, high hydrophobicity, multifunctionality, longevity, and intrinsic disorder. With recent advances in protein biophysical characterization and bioinformatics, it has become evident that intrinsically disordered proteins (IDPs) are abundant in myelin, and their flexible nature enables multifunctionality. Here, we review known myelin IDPs, their conservation, molecular characteristics and functions, and their disease relevance, along with open questions and speculations. We place emphasis on classifying the molecular details of IDPs in myelin and correlate these with their various functions, including susceptibility to post-translational modifications, function in protein-protein and protein-membrane interactions, as well as their role as extended entropic chains. We discuss how myelin pathology can relate to IDPs and which molecular factors are potentially involved.

How Does Protein Zero Assemble Compact Myelin?

“…The Ig-like domain is structurally very similar to the Ig-like domain in MPZL1, although they share only ~46% sequence identity [ 56 ]. P0ct differs drastically from the Ig-like domain, as it has a compositional bias typical for intrinsically disordered proteins (IDPs) [ 57 ] and is highly positively charged, much like MBP [ 12 , 17 ]. Systematic biophysical characterizations using simplified lipid compositions have been performed on P0ct, which revealed that P0ct alone is an IDP in solution but folds upon irreversible association with negatively charged detergent micelles and lipid vesicles [ 58 , 59 , 60 , 61 ].…”

“…Experimental evidence suggests that P0ct differs from MBP in one noteworthy aspect during membrane association: when MBP binds to a single membrane, a partially folded intermediate state is formed, which can further adhere to a second membrane given that MBP reaches a critical concentration [ 12 , 63 ]. On the other hand, P0ct as a free polypeptide completely embeds into model membranes ( Figure 3 a) [ 44 ]; however, more studies regarding the binding mode are needed.…”

“…When MBP performs its membrane stacking function, local translation of free MBP allows spontaneous interaction with membranes, and the formation of compact myelin [ 63 ]. On the other hand, when MBP remains soluble, it may have other functions [ 12 , 17 ]. The solubility of MBP distinguishes it from the expression pattern and trafficking of P0; P0ct is likely to always remain membrane-embedded and have less spatial freedom.…”

“…These in turn arise from the neural crest during early post-natal development along with other glial cells [ 10 ]—a proliferation pathway that is not present in the CNS. Oligodendrocytic myelination in the CNS is arranged differently to that in the PNS [ 11 ], although the mature myelin sheaths in both the CNS and PNS morphologically resemble each other [ 12 ].…”

“…CNS and PNS myelin are highly enriched in a mere handful of proteins, which is an unusual feature in most biological systems. Many of these proteins are multifunctional [ 15 , 16 , 17 , 18 , 19 , 20 , 21 ], contain large stretches of intrinsic disorder [ 12 ], tolerate highly hydrophobic conditions [ 22 ], and have extended lifetimes [ 23 ]. While there is some overlap between the CNS and PNS myelin proteomes [ 13 , 14 ], proteins that are specific either to the CNS or the PNS are present especially in compact myelin, which forms the insulative bulk of the myelin sheath.…”