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Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999.

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Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition.

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The Immunoglobulin Gene Superfamily

and .

Correspondence to David R. Colman, Brookdale Center for Molecular Biology, Box 1126, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029.

The best studied group of recognition/adhesion molecules expressed in the nervous system is that of the IgCAMs (Fig. 7-1), which are defined by regions that have sequence similarity with Igs, termed the Ig domains [3,4]. Ig domains contain alternating hydrophobic and hydrophilic stretches of residues, which form a series of antiparallel β strands. The β strands come together to form two β sheets. The folding of the β sheets is, in most cases, stabilized by the formation of a disulfide bond between the sheets. There are three subclasses of Ig-like domains, which are defined by their similarity to variable (V) or constant (C) regions of Igs. For V-like domains, there are 70 to 110 amino acids spanning the two cysteines that form the disulfide bond, allowing formation of seven to nine β strands. C-like domains have about 50 amino acids spanning the stabilizing cysteines and, consequently, carry seven β sheets. The third class of Ig-like domains is termed a C2 domain. This class of IgCAM has the β strand distribution of a C-like domain but bears more sequence similarity to V-like domains.

Figure 7-1. The immunoglobulin (Ig) gene family of molecules.

Figure 7-1

The immunoglobulin (Ig) gene family of molecules. Several varieties of Ig domain-containing molecules are contained within the Ig gene superfamily. Most are type I membrane proteins; some have only Ig domains or other moieties which may convey function (more...)

The formation of immunoglobulin-like domains may confer characteristics important for extracellular presentation and interaction with other molecules

First, because of the folding pattern, Ig domains are stabilized by both inward-pointing hydrophobic amino acids and the intersheet disulfide bond, making them relatively resistant to proteolysis and, hence, ideal molecules to present to the external cellular environment. Second, the folding of the β strands provides a good platform for the presentation of amino acids, carried in the loops between the strands, for interaction with an opposing molecule. The loops between β strands, in antibodies, carry the antigen-recognition sites and, in Ig-like domains, contain the regions of greatest variability, allowing for distinct and specific interactions.

Members of this family of molecules may have only one Ig-like domain, as is the case for the myelin protein P0, or, as for most of the family, have many Ig domains. In addition to the subclassification of Ig domains into V-, C- and C2-like domains, Ig family members can be broadly divided into three general classes [5]: (i) those that have only Ig-like domains; (ii) those that have Ig domains and additional domains that resemble regions of the ECM component fibronectin, termed FN-like domains; and (iii) those that have Ig domains and motifs other than FN-like domains. Moreover, any one Ig family member may have many isoforms, which may differ in the length of the cytoplasmic domain, in their post-translational modifications and whether they are membrane-spanning or glycophosphatidylinositol (GPI)-anchored proteins (see Box 3-1). Also, additional amino acid sequences inserted in the extracellular domain may distinguish isoforms of a particular IgCAM. While it is not known how the majority of different isoforms of a particular IgCAM affect its functioning, differences in effect have been described for molecules that carry some of the isoform-distinguishing amino acid sequences in the extracellular domain of the neural cell adhesion molecule (NCAM). For example, a sequence of ten amino acids, termed the variable alternative spliced exon (VASE) sequence, in the fourth Ig domain of some isoforms of NCAM alters the response of axonal growth to this adhesion molecule; NCAM proteins with the VASE sequence are much less effective at promoting axonal growth than are NCAM proteins without this sequence. However, a puzzling question is: How do IgCAMs that have identical extracellular domains, but are either GPI-linked or membrane-spanning, differ in function? Similarly, how differences in the cytoplasmic domain affect function is still not known. Presumably, the cytoplasmic domains interact with signal-transduction cascades and cytoskeletal proteins and in this way transduce adhesion into an intracellular response.

The siglecs constitute a novel subfamily of immunoglobulin-like molecules that bind to sialosides

These molecules, previously termed sialoadhesins, share considerable sequence similarity among the first four amino-terminal Ig domains [6]. More importantly, all members of this subfamily bind to sialoglycoconjugates. To date, only two siglecs have been identified in the nervous system: the myelin-associated glycoprotein (MAG) and the Schwann cell myelin protein (SMP) (see Chap. 4). All other family members are specific to the immune system. An additional common feature of this IgCAM subfamily is that they bind sialic acid with relatively low affinity. Because of this, it is suggested that siglecs must be clustered within the membrane and that the molecule(s) with which siglecs interact must either be clustered or carry multimeric sialic acid residues to be effective. It should be noted, however, that although both MAG and SMP have been shown to be sialic acid-binding proteins, the identity of a possible sialoglycoconjugate(s) with which they interact and the functional relevance of such an interaction have yet to be described.

Immunoglobulin-like cell adhesion molecules signal to the cytoplasm

In some instances, adhesion may act primarily to bind membranes to surfaces, but it now seems clear that some IgCAMs act via the cytoplasmic domain after engaging with a cognate partner molecule to initiate a signal-transduction cascade as a direct consequence of an adhesive interaction. A good example of this is the Trk receptors, which have two Ig domains in their extracellular sequences, or the fibroblast growth factor (FGF) receptor with four Ig-like domains, which first bind a neurotrophin, such as nerve growth factor (NGF), brain-derived growth factor (BDNF), neurotrophin 3 (NT3) or FGF (Chap. 19), after which signal transduction is triggered by dimerization and autophosphorylation of the cytoplasmic domains by endogenous tyrosine kinases (see Chap. 24). In contrast, in molecules such as NCAM and L1, which have multiple Ig domains, and P0, which has a single Ig domain, all of which are known to interact homophilically, there is no obvious mechanism whereby a signaling cascade could be initiated after interaction. None of these proteins carries endogenous tyrosine kinase activity or any motifs that might indicate an interaction with G proteins. A novel mechanism for signaling [7,8] has been suggested for NCAM, L1 and N-cadherin (see below) in that these molecules are believed, in certain circumstances, to cluster with the FGF receptor and induce autophosphorylation of that receptor in the absence of its usual ligand, FGF (Fig. 7-2). In contrast, the myelin P0 protein, although it has been suggested [9] to cluster within its membrane and interact, initially, with the cytoskeleton, is unlikely to initiate a signal-transduction cascade. The primary, if not the only, role of P0 is to hold the myelin membranes in a tightly compacted state (Chap. 4).

Figure 7-2. Signaling events in cell adhesion molecule (CAM)-stimulated neurite outgrowth.

Figure 7-2

Signaling events in cell adhesion molecule (CAM)-stimulated neurite outgrowth. It has been postulated that a signaling cascade is stimulated by homophilic interactions of neural cell adhesion molecule (NCAM), N-cadherin (NCAD) or L1, which dimerizes the (more...)

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 1999, American Society for Neurochemistry.
Bookshelf ID: NBK28187


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