Myelin management by the 18.5‐kDa and 21.5‐kDa classic myelin basic protein isoforms

Abstract

The classic myelin basic protein (MBP) splice isoforms range in nominal molecular mass from 14 to 21.5 kDa, and arise from the gene in the oligodendrocyte lineage (Golli) in maturing oligodendrocytes. The 18.5-kDa isoform that predominates in adult myelin adheres the cytosolic surfaces of oligodendrocyte membranes together, and forms a two-dimensional molecular sieve restricting protein diffusion into compact myelin. However, this protein has additional roles including cytoskeletal assembly and membrane extension, binding to SH3-domains, participation in Fyn-mediated signaling pathways, sequestration of phosphoinositides, and maintenance of calcium homeostasis. Of the diverse post-translational modifications of this isoform, phosphorylation is the most dynamic, and modulates 18.5-kDa MBP's protein-membrane and proteinprotein interactions, indicative of a rich repertoire of functions.In developing and mature myelin, phosphorylation can result in microdomain or even nuclear targeting of the protein, supporting the conclusion that 18.5-kDa MBP has significant roles beyond membrane adhesion. The full-length, early-developmental 21.5-kDa splice isoform is predominantly karyophilic due to a non-traditional P-Y nuclear localization signal, with effects such as promotion of oligodendrocyte proliferation. We discuss in vitro and recent in vivo evidence for multifunctionality of these classic basic proteins of myelin, and argue for a systematic evaluation of the temporal and spatial distributions of these protein isoforms, and their modified variants, during oligodendrocyte differentiation. Keywords: cytoskeleton, Fyn-SH3, intrinsically disordered protein, myelin basic protein, oligodendrocyte, phosphorylation. J. Neurochem. (2013) 125, 334-361. What is myelin basic protein and what does it do?The 'classic' 18.5-kDa isoform of myelin basic protein (MBP) was first isolated more than 50 years ago as an encephalitogenic determinant (Roboz-Einstein et al. 1962;Carnegie and Lumsden 1966). This protein is an integral component of central nervous system (CNS) myelin, adhering the cytoplasmic leaflets of the oligodendrocyte (OLG) membrane to each other to form the major dense line observed in electron micrographs (Trapp and Kidd 2004). This fundamental role is demonstrated by the shiverer mutant mouse which has an ablation in the MBP gene, and whose CNS myelin is sparse and relatively unstructured (Dupouey Received December 19, 2012; revised manuscript received February 5, 2013; accepted February 5, 2013. Address correspondence and reprint requests to George Harauz, Department of Molecular and Cellular Biology, University of Guelph, 50 Stone Road East, Guelph, Ontario, N1G 2W1, Canada. E-mail: gharauz@uoguelph.ca Abbreviations used: CaM, calmodulin; CNS, central nervous system; Golli, gene in the oligodendrocyte lineage; IDP, intrinsically disordered protein; MAPK, mitogen-activated protein kinase; MAP, microtubuleassociated protein; MBP, myelin basic protein; MoRF, molecular recognition fragment; NLS, nuclear locali...

Inflammaging impairs peripheral nerve maintenance and regeneration

“…The reduced pro‐inflammatory response was accompanied by improved remyelination, indicated by increased myelin protein zero (MPZ) signal in tissue sections (Figure 4e) and strong upregulation of the remyelination‐specific 21.5‐kDa isoform of myelin basic protein (MBP) (Harauz & Boggs, 2013) in whole nerve lysates (Figure 4f). Phosho‐ERK1/2 was slightly increased following ASA treatment, again indicating improved regeneration.…”

Structural Transition in Myelin Membrane as Initiator of Multiple Sclerosis

“…7,8 MBP, which represents about 10% of myelin by weight, is intrinsically disordered in solution. 9,10 When bound to a lipid surface, secondary structural elements form, and the hydrophobic parts of the protein are embedded in the bilayer. 11,12 Moreover, the bound MBP has been shown to adopt a compact "C" shape, 13 and to associate with neighboring MBPs to create a mesh-like structure within the cytoplasmic space.…”

Transcriptional Expression of Myelin Basic Protein in Oligodendrocytes Depends on Functional Syntaxin 4: a Potential Correlation with Autocrine Signaling

“…We therefore determined the extent to which VAMP3 and MBP mRNA were colocalizing in the cells, as examined by fluorescence colocalization. To visualize MBP mRNA, 48 short fluorescent probes were employed that specifically bind to the 14-kDa MBP, the major MBP isoform present in rodent myelin (22,24), and which allows for single MBP mRNA detection (56). As shown in Fig.…”

“…Furthermore, MBP appears to act as a portal for protein entry into myelin membranes (7). MBP is transported to the myelin sheath in its mRNA form (26,27), which is thought to circumvent premature adhesion of membranes (1,22,24,25). Although MBP mRNA is assembled in nonmembranous granules (26)(27)(28), a causal relationship with the vesicular transport ma-chinery is likely, given that membrane trafficking appears to be involved in RNA transport and/or anchoring (29)(30)(31).…”

“…These proteins are expressed in a timely fashion and sorted and transported to the myelin membrane by different mechanisms (1,20,21). MBP, located at the cytoplasmic surface of myelin membranes, is a basic, membrane-associated adhesive protein and essential for myelination in vivo (22)(23)(24). Its adhesive properties organize the close apposition of the inner membrane leaflets, leading to myelin compaction (25), essential for saltatory nerve conduction.…”