Proteins in myelin

Figure 15.4 Four compounds that are methylated either by SAM or methyl FH4 (CH3 FH4). The processes are (i) cytidine bases in DNA (11) methylatlon of deoxyUMP to produce deoxythymidine monophosphate (111) formation of phosphatidylcholine from phos-phatldylethanolamlne (Chapter 17) (Iv) methylatlon of a protein In myelin. The base cytidine Is methylated In DNA to produce methylcytidine which. If deamlnated, produces methylthymidine In DNA. Methylatlon of the bases can modify gene transcription (see text). (PR 5 -phosphor1bose).

Perry, L. L., Barzaga-Gilbert, E., and Trotter, J. L., T cell sensitization to proteolipid protein in myelin basic protein inducing relapsing experimental allergic encephalomyelitis. J. Neuroimmunol., 33, 7, 1991. 

Figure 7.7 Curve-fitted amide I band of myelin basic protein in myelin T, turns and bends P, -structure a, a-helix R, random coil configuration S, amino acid side-chain vibrations. From Stuart, B., Biological Applications of Infrared Spectroscopy, ACOL Series, Wiley, Chichester, UK, 1997. University of Greenwich, and reproduced by permission of the University of Greenwich.

Manczak M, Jiang S, Orzechowska B, Adamus G (2002) Crucial role of CCL3/MIP-1 alpha in the recurrence of autoimmune anterior uveitis induced with myelin basic protein in Lewis rats. J Autoimmun 18 259-270... 

DPDPB has been used to study the endocytosis of cadherin from intracellular junctions (Troyanovsky et al., 2006), the subunit arrangement in the flagellar rotor assembly (Lowder et al., 2005), and the disease-associated mutations in myelin proteolipid protein in the endoplasmic reticulum (ER) (Swanton et al., 2005). DPDPB can be used to conjugate reduced antibody molecules to p-D-galactosidase using essentially the same protocol as that described by O Sullivan et al. (1979). 

Swanton, E., Holland, A., High, S., and Woodman, P. (2005) Disease-associated mutations cause premature oligomerization of myelin proteolipid protein in the endoplasmic reticulum. PNAS 102, 4342-4347. 

The principal difference in the overall protein composition of PNS and CNS myelin is that P0 replaces PLP as the major protein, although myelin-forming Schwann cells do express very low levels of PLP. It is interesting to note that PLP and P0 proteins, which are so different in sequence, post-translational modifications and membrane topology, may have similar roles in the formation of structures as closely related as myelin of the CNS and PNS respectively. Expression of P0 in transfected cells results in cell-cell interactions that are due to homophilic binding... 

P2 protein. PNS myelin contains a positively charged protein different from MBP that is referred to as P2 (Mr — 15,000). It is unrelated in sequence to MBP and is a member of a family of cytoplasmic fatty acid binding proteins (FABP) that are present in a variety of cell types [25]. The amount of P2 protein is variable among species, accounting for about 15% of total protein in bovine PNS myelin, 5% in humans and less than 1% in rodents. P2 protein is generally considered a PNS myelin protein but it is expressed in small amounts in CNS myelin sheaths of some species. P2 is an antigen for experimental allergic neuritis, the PNS counterpart of EAE (see Chs 36 and 38). P2 appears to be present in the major dense line of myelin sheaths, where it may play a structural role similar to MBP... 

Fig. 4-11). Interestingly, the larger amounts of P2 protein that are in myelin of some species correlate with increased widths of the major dense lines as determined by X-ray diffraction, and there appears to be substantially more P2 in large sheaths than small ones [4]. The large variation in the amount and distribution of the protein from species to species and sheath to sheath raises so far unanswered questions about its function. Its similarities to cytoplasmic proteins in other cells, whose functions appear to involve solubilization and transport of fatty acids and retinoids, suggest that it might function similarly in myelin assembly or turnover, but there is currently no direct experimental evidence to support this hypothesis. 

Myelin basic protein. In PNS myelin, MBP varies from approximately 5% to 18% of total protein, in contrast to the CNS, where it is close to 30% [ 1 ]. In rodents, the same four 21,18.5,17 and 14kDa MBPs found in the CNS are present in the PNS. In adult rodents, the 14kDa MBP is the most prominent component and is termed Pr in the PNS nomenclature. The 18.5 kDa component is present and is often referred to as the P, protein in the nomenclature of peripheral myelin proteins. Another species-specific variation in human PNS is that the major basic protein is not the 18.5 kDa isoform that is most prominent in the CNS but rather a form of about 17 kDa. It appears that MBP does not play as critical a role in myelin structure in the PNS as it does in the CNS. For example, the shiverer mutant mouse, which expresses no MBP (Table 4-2), has a greatly reduced amount of CNS myelin, with no compaction of the major dense line. By contrast, shiverer PNS has essentially normal myelin,both in amount and structure, despite the absence of MBP. This CNS/PNS difference in the role of MBP is probably because the cytoplasmic domain of P0 has an important role in stabilizing the major dense line of PNS myelin. Animals doubly deficient for P0 and MBP have a more severe defect in compaction of the PNS major dense line than P0-null mice, which indicates that both proteins contribute to compaction of the cytoplasmic surfaces in PNS myelin [23],... 

Myelin sheaths contain other proteins, some of which have only recently been established as myelin-related. The proteins described above represent most of the well-established myelin proteins that are myelin-specific or have been studied primarily in the context of myelin and demyelinating diseases. However, myelin sheaths contain numerous other proteins in smaller amounts that are also in many other cells and/or have only been identified relatively recently. Some of these are in compact myelin but others are enriched in specialized... 

A few enzymes, such as the previously mentioned CNP, are believed to be fairly specific for myelin/oligodendro-cytes. There is much more in the CNS than in peripheral nerve, suggesting some function more specialized to the CNS. In addition, a unique pH 7.2 cholesterol ester hydrolase is also enriched in myelin. On the other hand, there are many enzymes that are not myelin-specific but appear to be intrinsic to myelin and not contaminants. These include cAMP-stimulated kinase, calcium/calmodulin-dependent kinase, protein kinase C, a neutral protease activity and phosphoprotein phosphatases. The protein kinase C and phosphatase activities are presumed to be responsible for the rapid turnover of MBP phosphate groups, and the PLP acylation enzyme activity is also intrinsic to myelin. 

Other enzymes present in myelin include those involved in phosphoinositide metabolism phosphatidylinositol kinase, diphosphoinositide kinase, the corresponding phosphatases and diglyceride kinases. These are of interest because of the high concentration of polyphosphoinositides of myelin and the rapid turnover of their phosphate groups. This area of research has expanded towards characterization of signal transduction system(s), with evidence of G proteins and phospholipases C and D in myelin. 

Other myelin-related proteins. Another protein in compact CNS myelin is the myelin-associated oligodendro-cytic basic protein, which is localized in the major dense line in several 8-12 kDa isoforms and appears to function in controlling axonal diameter and the arrangement of the radial component [39]. PNS myelin sheaths have long... 

Small amounts of proteins characteristic of cells and membranes in general can also be found in myelin. There is evidence that tubulin is an authentic myelin-related component (Fig. 4-12B, D, CNS myelin). The 48kDa myelin/oligodendrocyte-specific protein (MOSP) is a component found only in CNS myelin and oligodendroglial membranes, which appears to associate with tubulin [41]. 

Stecca, B., Southwood, C. M., Gragerov, A. et al. The evolution of lipophilin genes from invertebrates to tetrapods DM-20 cannot replace proteolipid protein in CNS myelin. /. Neurosci. 20,4002-4010, 2000. 

Martenson, R. and Uyemura, K. Myelin P2, a neuritogenic member of the family of cytoplasmic lipid binding proteins. In R. E. Martenson (ed.), Myelin biology and chemistry. Boca Raton, FL CRC Press, 1992, pp. 509-530. 

Bronstein, J. M. Function of tetraspan proteins in the myelin sheath. Curr. Opin. Neurobiol. 10, 552-557, 2000. 

Erne, B., Sansano, S., Frank, M. et al. Rafts in adult peripheral nerve myelin contain major structural myelin proteins and myelin and lymphocyte protein (MAL) and CD59 as specific markers. /. Neurochem. 82, 550-562, 2002. 

Not all neurons have NFs. Indeed, one entire phylum in the animal kingdom, arthropods, expresses only type V nuclear lamins so arthropod cells have no IF cytoskeletal structures at all. In addition, mature oligodendrocytes lack IFs although their embryonic precursors contain vimentin. Clearly, the IFs are not essential for cell survival. Yet, in large myelinated fibers, NFs make up the bulk of axonal volume and represent a substantial fraction of the total protein in brain. In most organisms, IFs in both glia... 

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