Definition
One of the two major classes of myelin proteins is the myelin basic proteins (MBPs), a family of proteins derived by alternative splicing of the MBP gene.
Discovery
Campagnoni et al identified a novel transcription unit of 105 kbp (called the Golli-mbp gene) that encompasses the mouse myelin basic protein (MBP) gene. Three unique exons within this gene are alternatively spliced into MBP exons and introns to produce a family of MBP gene- related mRNAs that are under individual developmental regulation. These mRNAs are temporally expressed within cells of the oligodendrocyte lineage at progressive stages of differentiation. Thus, the MBP gene is a part of a more complex gene structure, the products of which play a role in oligodendrocyte differentiation prior to myelination1.
Structural Characteristics
There are multiple isoforms of MBP that are produced through the translation of separate mRNAs, resulting in a heterogeneous population of MBP structures. MBP is an ‘intrinsically unstructured’ protein with a high proportion ( 75%) of random coil, but postulated to have core elements of ß-sheet and a-helix. In solution, MBP is “intrinsically unstructured” (or “natively unfolded”). Upon binding to detergents or lipids, the levels of beta-sheet and especially alpha-helical structure increase dramatically. MBP was an amphipathic alpha-helix located at the interface between the oligodendrocyte cytoplasm and the membrane. In a solution circular dichroism (CD) and Fourier transform infrared spectroscopic study, MBP peptides were found to have both helix and sheet structures in methanol, with the latter increasing in amount in progressively shorter peptides 2, 3.
Mode of Action
In order to clarify insulinotropic effects of the myelin basic protein (MBP) Kolehmainen et al studied mode of association and distribution of MBP in the pancreatic islets and tested the insulin-releasing activity of various MBP peptides. Rat pancreatic islets were first stimulated in a static incubation with 10 µM bovine MBP (bMBP) at a substimulatory (3.5 mM) glucose concentration. The islets exposed to MBP released significantly more insulin and glucagon in a second incubation in the absence of added stimulant and in the presence of 11.5 mM arginine than the incubated, non-stimulated islets and islets initially stimulated with 15 mM glucose. Response to stimulation with 15 mM glucose in the second incubation by islets exposed first to MBP was impaired compared to incubated, non-stimulated islets. Immunoelectron microscopy showed that MBP had entered into the islet cells and associated with membranes of intracellular vacuoles, most of which represented enlarged, often fused insulin granules. MBP was also present at the islet edge and in the intercellular spaces. Of the purified MBP peptides of sizes of 4.8–13.6 kDa, produced from the digestion with brain acid proteinase and with pepsin and covering the entire bMBP sequence, only the large peptides (1–88, 9.8 kDa and 43–169, 13.6 kDa) stimulated insulin secretion significantly. Heterogeneous peptide mixtures, obtained from a time-course digestion of bMBP by myelin calcium-activated neutral protease, consisting of peptides of approximate molecular weights of 8–11 kDa and larger, also stimulated insulin release. The glucagon-releasing activity of MBP peptides was low and followed the same pattern as the insulin-releasing activity. These results suggest that MBP-induced fusion of the membranes of hormone granules is involved in MBP-induced insulin release. The hormone-releasing activity of the large peptides in addition to that of the intact molecule is explained as being due to the ability of these peptides to associate with membranes. MBP-induced hormone release and related effects could be associated with neuropathological conditions such as stroke and multiple sclerosis 4.
Functions
MBP plays a key role in the pathology of MS, although its mechanism of action has remained unclear. Antigenically related MBP was isolated from the cerebrospinal fluid of patients with multiple sclerosis (MS) 5. Induction of experimental allergic encephalomyelitis (EAE) with MBP produced a monophasic inflammatory disease process in guinea pigs with minimal demyelination, whereas the addition of galactocerebrosides or the use of whole myelin produced EAE with demyelination, suggesting that MBP plays a role in demyelination when in synergy with myelin lipids 6. It was demonstrated that a single transfer of MBP-sensitized T cells from animals with EAE produced a relapsing disease process in mice with both inflammation and demyelination, similar to what is found in MS. This discovery suggests MBP isoforms as candidate autoantigens7.
References
1. Campagnoni AT, Pribyl TM, Campagnoni CW, Kampf K, Amur- Umarjee S, Landry CF, Handley VW, Newman SL, Garbay B, Kitamura K (1993). Structure and developmental regulation of golli-mbp, a 105 kb gene that encompasses the myelin basic protein gene and is expressed in cells in the oligodendrocyte lineage in the brain. J Biol Chem., 268: 4930-4938.
2. Hill CM, Bates IR, White GF, Hallett, FR, Harauz G (2002). Effects of the osmolyte trimethylamine-N-oxide on conformation, self-association, and two-dimensional crystallization of myelin basic protein. J Struct Biol., 139: 13-26.
3. Whitaker JN, Moscarello MA, Herman PK, Epand RM, Surewicz, WK (1990) Conformational correlates of the epitopes of human myelin basic protein peptide 80-89. J. Neurochem., 55:568-576.
4. Kolehmainen E. (1995). Evidence supporting membrane fusion as the mechanism of myelin basic protein-induced insulin release from rat pancreatic islets. Neurochem Intl., 26 (5):503-518.
5. Carson JH, Barbarese E, Braun PE, McPherson TA (1978). Components in multiple sclerosis cerebrospinal fluid that are detected by radioimmunoassay for myelin basic protein. PNAS, 75(4):1976–1978.
6. Raine CS, Traugott U, Farooq M, Bornstein MB, Norton WT (1981). Augmentation of immune-mediated demyelination by lipid haptens. Lab. Invest., 45:174–182.
7. Mokhtarian F, McFarlin DE, Raine CS (1984). Adoptive transfer of myelin basic protein-sensitized T cells produces chronic relapsing demyelinating disease in mice. Nature, 309:356–358.