Structure and Function of the Myelin Proteins: Current Status and Perspectives in Relation to Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination and loss of neurological function, local macrophage infiltrate and neuroantigenspecific CD4 + T cells. MS arises from complex interactions between genetic, immunological, infective and biochemical mechanisms. Although the circumstances of MS etiology remain hypothetical, one persistent theme involves immune system recognition of myelin-specific antigens derived from myelin basic protein, the most abundant extrinsic myelin membrane protein, and/or another equally suitable myelin protein or lipid. Knowledge of the biochemical and physico-chemical properties of myelin proteins and lipids, particularly their composition, organization, structure and accessibility with respect to the compacted myelin multilayers, becomes central to understanding how and why myelin-specific antigens become selected during the development of MS. This review focuses on the current understanding of the molecular basis of MS with emphasis: (i) on the physical-chemical properties, organization, morphology, and accessibility of the proteins and lipids within the myelin multilayers; (ii) on the structure-function relationships and characterization of the myelin proteins relevant to the manifestation and evolution of MS; (iii) on conformational relationships between myelin epitopes which might become selected during the development of MS; (iv) on the structure of MHC/HLA in complex with MBP peptides as well as with TCR, which is crucial to the understanding of the pathogenesis of MS with the ultimate goal of designed antigen-specific treatments.

Gender effect on neurodegeneration and myelin markers in an animal model for multiple sclerosis

“…In particular, mRNA expression level was analyzed for PDGFαR, which is a marker for the oligodendrocyte precursor cells (OPCs) responsible for myelin repair in the mature CNS [22] and MBP, which is one of the most abundant among the myelin proteins [23]. In the spinal cord, PDGFαR mRNA expression in healthy males is around 2.5 times higher than in healthy females (p = 0.0175), whereas the MBP mRNA level is 5 times higher in males than in females (p = 0.0004) (Figure 3A, B).…”

Myelin basic protein: a multifunctional protein

“…Accessibility of different residues to the micelle interior and aqueous phase was similar to results from EPR spectroscopy of spin-labeled rmC1 using lipid bilayers. The structure of several antigenic epitopes from MBP in aqueous solution, and when bound to class II major histocompatibility complex (MHC) proteins, has been reviewed recently [143]. Conversion of six Arg/Lys (R25, R33, K119, R127, R157, R168) to Gln in rmC1, to mimic citrullination, yielding recombinant murine C8 (rmC8), resulted in dissociation of the C-terminal half of the intact spin-labeled protein from the lipid bilayer, whereas the N-terminal half remained bound and embedded in the bilayer (Fig.…”

A Tale of Two Citrullines—Structural and Functional Aspects of Myelin Basic Protein Deimination in Health and Disease

“…One of the candidate autoantigens in MS is MBP, because of its early identification as an agent that can induce EAE in a susceptible host [235]. The cerebrospinal fluid of patients with MS contains both MBP-derived peptides [236] and elevated levels of autoantibodies to MBP [237][238][239][240][241][242][243], inspiring strategies for MS immunotherapy by injection of synthetic MBP peptides [243][244][245][246].…”