Amino Acid Sequence of the Basic Protein of the Myelin Membrane
01 Nov 1970-Proceedings of the National Academy of Sciences of the United States of America (National Academy of Sciences)-Vol. 67, Iss: 3, pp 1425-1431
TL;DR: The amino acid sequences of the encephalitogenic basic protein, A1, from bovine and human myelin are similar, differing by only 11 residues, and the sequence reveals that while basic residues are spread randomly over most of the polypeptide chain, several regions exist that are nonpolar in character.
Abstract: The amino acid sequences of the encephalitogenic basic protein, A1, from bovine and human myelin are similar, differing by only 11 residues. The sequence reveals that while basic residues are spread randomly over most of the polypeptide chain, several regions (8-10 residues) exist that are nonpolar in character. The bovine protein has 170 residues with molecular weight 18,400. The human protein, which has an additional His-Gly sequence, contains 172 residues. The major encephalitogenic determinant (tryptophan region) of the bovine protein differs from the human only by a lysine to arginine substitution. The structural features of the A1 protein are discussed, with special reference to its role in stabilization of the myelin membrane, and its relation to multiple sclerosis.
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TL;DR: It was found that crude myelin fractions are highly enriched in mRNAs coding for the MBPs but not in mRNA coding for PLP, which suggests that whereas the bound polysomes synthesizing PLP are largely confined to the cell body, free polysome synthesizing MBPs are concentrated in oligodendrocyte processes involved in myelination, which explains the immediate incorporation of MBPs into the developing myelin sheath.
Abstract: The distribution of newly synthesized proteolipid protein (PLP, 23 kdaltons) and myelin basic proteins (MBPs, 14-21.5 kdaltons) was determined in microsomal and myelin fractions prepared from the brainstems o1 10-30 d-old rats sacrificed at different times after an intracranial injection of 35S-methionine. Labeled MBPs were found in the myelin fraction 2 min after the injection, whereas PLP appeared first in the rough microsomal fraction and only after a lag of 30 min in the myelin fraction. Cell-free translation experiments using purified mRNAs demonstrated that PLP and MBPs are synthesized in bound and free polysomes, respectively. A mechanism involving the cotranslational insertion into the ER membrane and subsequent passage of the polypeptides through the Golgi apparatus is consistent with the lag observed in the appearance of the in vivo-labeled PLP in the myelin membrane. Newly synthesized PLP and MBPs are not proteolytically processed, because the primary translation products synthesized in vitro had the same electrophoretic mobility and N-terminal amino acid sequence as the mature PLP and MBP polypeptides. It was found that crude myelin fractions are highly enriched in mRNAs coding for the MBPs but not in mRNA coding for PLP. This suggests that whereas the bound polysomes synthesizing PLP are largely confined to the cell body, free polysomes synthesizing MBPs are concentrated in oligodendrocyte processes involved in myelination, which explains the immediate incorporation of MBPs into the developing myelin sheath.
429 citations
TL;DR: The over-all sequence reveals no obvious periodicity but rather a general distribution of basic residues over the polypeptide chain, making the interaction with phospholipids within the myelin matrix highly probable.
333 citations
TL;DR: Analysis of soluble Ehrlich ascites proteins by the Sanger procedure revealed methionine, alanine, valine, and glycine as the major NH2-terminal amino acids, and results suggest that approximately 80% of the soluble proteins from Ehrich ascites cells contain acetate at their NH2 -terminal residues.
261 citations
TL;DR: The relationship between the normal state of self-tolerance and its abnormal corollary, autoimmunity is presented and the pathogenic mechanisms that may be involved in autoimmune disease are examined in the light of two familiar experimental models.
Abstract: Publisher Summary This chapter presents the relationship between the normal state of self-tolerance and its abnormal corollary, autoimmunity. The several possible bases for loss of self-tolerance, including failure of immune regulation and abnormal presentation of potential self-antigens, are considered in terms of current understanding of cellular and humoral immune processes. A particularly thorough evaluation of suppressor cells and their possible role in self-tolerance and autoimmunity is presented. The pathogenic mechanisms that may be involved in autoimmune disease are examined in the light of two familiar experimental models, allergic encephalomyelitis and autoimmune thyroiditis. The pathogenic potential of cellular autoimmune responses in encephalomyelitis, on the one hand, and of autoantibody responses in thyroiditis, on the other, indicates the very different pathogeneses, which may operate in autoimmunity. The various mechanisms that are responsible for the loss of tolerance to self antigens can be divided into three general categories. First, abnormalities may occur in the regulatory mechanisms that control the normal immune response. Second, a component of self that was once sequestered and nonimmunogenic may become exposed and presented in an antigenic form to the immune system. Third, a normally tolerated self component may for some reason circumvent the prevailing regulatory mechanisms and activate one or more arms of a normal immune system. Numerous factors are involved in autoimmune diseases including genetic control at major histocompatibility complex (MHC) and non-MHC loci, immunologic regulatory mechanisms, self-nonself recognition, and logistics and/or nature of the target autoantigens.
239 citations
TL;DR: Myelinogenesis has proven to be very useful system in which to examine cellular and molecular mechanisms regulating the activity of a nervous system-specific process, and the importance of epigenetic factors in modulating myelin protein gene expression.
Abstract: The cellular and molecular aspects of myelin protein metabolism have recently been among the most intensively studied in neurobiology. Myelination is a developmentally regulated process involving the coordination of expression of genes encoding both myelin proteins and the enzymes involved in myelin lipid metabolism. In the central nervous system, the oligodendrocyte plasma membrane elaborates prodigious amounts of myelin over a relatively short developmental period. During development, myelin undergoes characteristic biochemical changes, presumably correlated with the morphological changes during its maturation from loosely-whorled bilayers to the thick multilamellar structure typical of the adult membrane. Genes encoding four myelin proteins have been isolated, and each of these specifies families of polypeptide isoforms synthesized from mRNAs derived through alternative splicing of the primary gene transcripts. In most cases, the production of the alternatively spliced transcripts is developmentally regulated, leading to the observed protein compositional changes in myelin. The chromosomal localizations of several of the myelin protein genes have been mapped in mice and humans, and abnormalities in two separate genes appear to be the genetic defects in the murine dysmyelinating mutants, shiverer and jimpy. Insertion of a normal myelin basic protein gene into the shiverer genome appears to correct many of the clinical and cell biological abnormalities associated with the defect. Most of the dysmyelinating mutants, including those in which the genetic defect is established, appear to exhibit pleiotropy with respect to the expression of other myelin genes. Post-translational events also appear to be important in myelin assembly and metabolism. The major myelin proteins are synthesized at different subcellular locations and follow different routes of assembly into the membrane. Prevention of certain post-translational modifications of some myelin proteins can result in the disruption of myelin structure, reminiscent of naturally occurring myelin disorders. Studies on the expression of myelin genes in tissue culture have shown the importance of epigenetic factors (e.g., hormones, growth factors, and cell-cell interactions) in modulating myelin protein gene expression. Thus, myelinogenesis has proven to be very useful system in which to examine cellular and molecular mechanisms regulating the activity of a nervous system-specific process.
223 citations