Molecular cloning and primary structure of myelin-associated glycoprotein (original) (raw)
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Differential expression of MAG isoforms during development
Journal of Neuroscience Research, 1991
The myelin-associated glycoproteins (MAG) mediate the cell interactions of oligodendrocytes and Schwann cells with axons that are myelinated. MAG exists in two developmentally regulated isoforms: large MAG (L-MAG) and small MAG (S-MAG). In this paper, we have studied the tissue-specific and developmentally regulated alternative splicing of these isoforms using monospecific antibodies that recognize epitopes common to both isoforms or that are present only on L-MAG. In the central nervous system (CNS), L-MAG is the major form synthesized early in development, and it persists as a significant proportion of the MAG present in the adult. In the peripheral nervous system (PNS), L-MAG is expressed at modest levels during development; it is virtually absent in the adult. Thus, the expression of L-MAG is not limited to the CNS, as was formerly believed, suggesting that it plays a common role during the early stages of myelin formation by both oligodendrocytes and Schwann cells. In both the CNS and PNS, S-MAG is the predominant isoform in the adult. A higher-molecular-weight form of MAG is present in the PNS at low abundance, that is developmentally regulated, and appears to be a glycosylation variant. An analysis of the carbohydrate residues on MAG demonstrates that it contains both N-linked and O-linked sugars that could be modulated during development. These results suggest a possible mechanism for the regulation of MAG function during myelinogenesis via the expression of alternative isoforms and carbohydrate modifications.
Molecular and Cellular Neuroscience, 2006
The two myelin-associated glycoprotein (MAG) isoforms are cell adhesion molecules that differ only in their cytoplasmic domains, but their specific roles are not well understood. In this study, we present a transgenic mouse line that specifically expresses GFP-tagged S-MAG correctly regulated and targeted into the myelin sheath allowing the specific discrimination of L-and S-MAG on the subcellular level. Here, we describe the differential expression pattern and spatial distribution of L-and S-MAG during development as well as in the adult central and peripheral nervous system. In peripheral nerves, where S-MAG is the sole isoform, we observed S-MAG concentrated in different ring-like structures such as periaxonal and abaxonal rings, and discs spanning through the compact myelin sheath perpendicular to the axon. In summary, our data provide new insight in the subcellular distribution of the two isoforms fundamental for the understanding of their specific functions in myelin formation and maintenance. D
Structural basis of myelin-associated glycoprotein adhesion and signalling
Nature Communications, 2016
Myelin-associated glycoprotein (MAG) is a myelin-expressed cell-adhesion and bi-directional signalling molecule. MAG maintains the myelin-axon spacing by interacting with specific neuronal glycolipids (gangliosides), inhibits axon regeneration and controls myelin formation. The mechanisms underlying MAG adhesion and signalling are unresolved. We present crystal structures of the MAG full ectodomain, which reveal an extended conformation of five Ig domains and a homodimeric arrangement involving membrane-proximal domains Ig4 and Ig5. MAG-oligosaccharide complex structures and biophysical assays show how MAG engages axonal gangliosides at domain Ig1. Two post-translational modifications were identified-N-linked glycosylation at the dimerization interface and tryptophan C-mannosylation proximal to the ganglioside binding site-that appear to have regulatory functions. Structure-guided mutations and neurite outgrowth assays demonstrate MAG dimerization and carbohydrate recognition are essential for its regeneration-inhibiting properties. The combination of trans ganglioside binding and cis homodimerization explains how MAG maintains the myelin-axon spacing and provides a mechanism for MAG-mediated bi-directional signalling.
The Journal of cell biology, 1987
The myelin associated glycoproteins (MAG) are integral plasma membrane proteins which are found in oligodendrocytes and Schwann cells and are believed to mediate the axonal-glial interactions of myelination. In this paper we demonstrate the existence in central nervous system myelin of two MAG polypeptides with Mrs of 67,000 and 72,000 that we have designated small MAG (S-MAG) and large MAG (L-MAG), respectively. The complete amino acid sequence of L-MAG and a partial amino acid sequence of S-MAG have been deduced from the nucleotide sequences of corresponding cDNA clones isolated from a lambda gt11 rat brain expression library. Based on their amino acid sequences, we predict that both proteins have an identical membrane spanning segment and a large extracellular domain. The putative extracellular region contains an Arg-Gly-Asp sequence that may be involved in the interaction of these proteins with the axon. The extracellular portion of L-MAG also contains five segments of internal ...
Journal of Cell Biology, 1990
The myelin-associated glycoproteins (MAG) are members of the immunoglobulin gene superfamily that function in the cell interactions of myelinating glial cells with axons. In this paper, we have characterized the structural features of these proteins. The disposition of MAG in the bilayer as a type 1 integral membrane protein (with an extracellularly disposed amino terminus, single transmembrane segment, and cytoplasmic carboxy terminus) was demonstrated in protease protection studies of MAG cotranslationally inserted into microsomes in vitro and in immunofluorescent studies with site specific antibodies. A genetically engineered MAG cDNA, which lacks the putative membrane spanning segment, was constructed and shown to encode a secreted protein.
Organization of Myelin Protein Genes: Myelin-Associated Glycoprotein
Annals of the New York Academy of Sciences, 1990
Myelinogenesis requires an orchestrated series of cellular events to generate and compact concentric layers of the oligodendrocyte or Schwann cell membrane around an axon. The regulation and modulation of interactions between cell membranes and between adjacent cell surfaces have particular importance in the elaboration of the myelin sheath. The myelin component myelin-associated glycoprotein (MAG) has been implicated as a key molecule in cell-cell interactions during myelinogenesis.1*2 The potential function of MAG as a cell adhesion molecule is also indicated by studies of cell adhesion in uitro3 as well as by its structural resemblance to more defined cell adhesion molecules such as N-CAM. This article reviews our studies on the structure and genetics of MAG.
European Journal of Neuroscience, 1993
The functional topography of the myelin-associated glycoprotein (MAG) was investigated by electron microscopic analysis of rotary-shadowed molecules of a MAG fragment (MAG 90) comprising the five immunoglobulin-like domains of the extracellular part of the molecule. MAG 90 molecules appeared as rod-like structures (18.5 +/- 1.2 nm long and 4.0 +/- 0.8 nm wide) with a globular domain at one end. Antibodies directed against the amino- and carboxy-terminus of MAG 90 interacted with the non-globular terminal region, indicating that the molecule is bent in the globular region with the amino- and carboxy-terminal arms in close apposition to each other. An antibody which interferes with the binding of MAG to neurons interacted predominantly with the globular domain of MAG 90. The fibril-forming collagen types I, III and V bound mainly to the non-globular terminal region of MAG 90, whereas the majority of heparin molecules interacted with the globular region of the molecule. The L2/HNK-1 carbohydrate structure was localized at the non-globular region in the protein fragment comprising the fourth and fifth immunoglobulin-like domains.
Structure and Function of the MyelinâAssociated Glycoproteinsa
Annals of the New York Academy of Sciences, 1990
Axons exhibit complex, reciprocal interactions with myelinating glial cells, that is, Schwann cells in the peripheral nervous system (PNS) and oligodendrocytes in the central nervous system (CNS). Contact with the axon regulates the proliferation of these glial cells and determines their state of differentiation, most dramatically their elaboration and maintenance of the myelin sheath. The glial cell, in turn, influences both the topographic segregation of axonal membrane constituents and the diameter of the adjacent axonal segment. These axonal-glial interactions are essential for the formation of a mature, fully differentiated myelinated nerve fiber, an essential component of the vertebrate nervous system.' This intimate functional interrelationship is, in turn, reflected in the close apposition of the respective plasma membranes of the axon and the myelinating glial cell. These membranes are separated by a regular extracellular space of 120-140 angstroms that is actively maintained even in pathologic conditions.2 The panoply of cell surface proteins present on the apposed membranes is likely to mediate these cellular interactions as well as maintain the periaxonal space. In addition, as they are extracellularly disposed, these proteins are potential targets in viral and immune-mediated damage to myelinated fibers. Identification and characterization of these membrane constituents should therefore provide important insights into the molecular mechanisms of these cell-cell interactions and into the pathogenesis of demyelinating diseases such as multiple sclerosis. Of the currently identified cell surface constituents of myelinating glial cells, the myelin-associated glycoproteins (MAG proteins) are the most likely candidates for mediating this interaction. These proteins are integral membrane proteins that are minor constiuents of the myelin sheath, comprising about 1% of the total protein content of CNS myelin and less than one tenth of that in PNS ~n y e l i n .~ Unlike structural components of compact myelin, such as the basic proteins or the proteolipid protein, the MAG proteins are present in noncompacted myelin membranes on the basis of fractionation studies as well as immuno-0 These studies were aided by basic research grant No.
Structure and Function of the Myelin-Associated Glycoproteins
Annals of the New York Academy of Sciences, 1990
Axons exhibit complex, reciprocal interactions with myelinating glial cells, that is, Schwann cells in the peripheral nervous system (PNS) and oligodendrocytes in the central nervous system (CNS). Contact with the axon regulates the proliferation of these glial cells and determines their state of differentiation, most dramatically their elaboration and maintenance of the myelin sheath. The glial cell, in turn, influences both the topographic segregation of axonal membrane constituents and the diameter of the adjacent axonal segment. These axonal-glial interactions are essential for the formation of a mature, fully differentiated myelinated nerve fiber, an essential component of the vertebrate nervous system.'