Ig-like domains

The extracellular domain of cadherins consists of a variable number of a repeated sequence of about 110 amino acids. This sequence is termed the cadherin repeat and resembles in overall structure, but not in sequence, the Ig like domains. The cadherin repeat is the characteristic motive common to all members of the cadherin superfamily. Classical and desmosomal cadherins contain five cadherin repeats, but as many as 34 repeats have been found in the FAT cadherin (see below). Cadherins are calcium-dependent cell adhesion molecules, which means that removal of Ca2+, e.g., by chelating agents such as EDTA, leads to loss of cadherin function. The Ca2+-binding pockets are made up of amino acids from two consecutive cadherin repeats, which form a characteristic tertiary structure to coordinate a single Ca2+ion [1]. 

FIGURE 4.7 Structure of the dimeric complex between FGF2 and FGF receptor 1. The Ig-like domains 2 and 3 of the two FGF receptor 1 molecules are composed of parallel p sheets and they are shown in medium and light gray, respectively. The two FGF2 molecules are composed of a bundle of p sheets that are shown in dark gray. PDB id 1CVS. (Plotnikov, A. N. et al., Cell, 98, 641, 1999.)... 

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 [8] (a) those that have only Ig-like domains (b) those that have Ig domains and additional domains that resemble regions of the ECM component fibronectin, termed FN-like domains and (c) 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 glycosylphos-phatidylinositol (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... 

The FCGR2A gene contains a second polymorphic site. CA-to-GA mutation results in a glutamine or tryptophan at amino acid position 27 in the membrane distal Ig-like domain. However, this substitution does not affect the Fc RIIa affinity for IgG (5,6). 

Figure 31-4 Schematic structure of one-fifth of an IgM molecule. From Putnam et al A (A) Covalent structure. (B) Schematic three-dimensional representation. (C) Ribbon diagram of an IgG molecule. From Cochran et al,64a (D) Folding patterns of one chain in a constant and a variable domain of a Bence-Jones protein. From Schiffer et al.66 Green arrows indicate hypervariable regions. (E) MolScript drawing of the common core structure of Ig-like domains. The lighter shaded strands (b, c, e, f) form the core common to all Ig-like domains, which is surrounded by structurally more varied additional strands (darker). The front sheet has up to five strands (a, f, c, e, c") and the back sheet up to four (a, b, e, d). Strand c" is very flexible and is not always a part of the (3 sheet. From Bork, Holm, and Sander.65 See also Fig. 2-16.

Salmikangas, P., Mykkanen, O. M., Gronholm, M., Heiska, L., Kere, J., and Carpen, O. (1999). Myotilin, a novel sarcomeric protein with two Ig-like domains, is encoded by a candidate gene for limb-girdle muscular dystrophy. Hum. Mol. Genet. 8, 1329-1336. 

G-protein (MyBP-C) has a substructure that is in many ways similar to parts of titin. Some of its domains are Fn3-like and Ig-like domains, but there are also unique sequences. The cardiac and skeletal forms of C-protein are also different (Fig. 21B). The skeletal form has 10 domains in which the G-terminal domains C8, G9, and CIO are associated with myosin and titin binding. CIO is the main myosin binding site, but C8 and G9 are needed to give C-protein its proper location on the myosin filament. Between Cl and C2 is a sequence that can bind to myosin S2... 

The NRG1-ICD is essential for surface expression of Type I Nrg l(Liu et al., 1998a). In vitro experiments demonstrate that Type I isoforms of NRG 1 lacking an intact intracellular domain fail to be expressed at the cell surface, and therefore fail to release soluble growth factor. Because the Type I NRG1 isoform is required for cardiac development, the so-called transmembrane mutant animals, the pan-knockout animals, and the Ig-mutant animals (in which the Ig-like domain common to all Type I and Type II isoforms is disrupted) all show the same embryonic lethal phenotype. 

Aasland, D., Oppmann, B., Grotzinger, J., Rose-John, S., and Kallen, K. J. (2002). The upper cytokine-binding module and the Ig-like domain of the leukaemia inhibitory factor (LIF) receptor are sufficient for a functional LIF receptor complex. J. Mol. Biol. 315, 637-646. 

The extracellular domain of Trk receptors is made up of three leucine-rich 24 residue motifs flanked on either side by a cysteine cluster (Cl is on the outer side and C2 is in the inner side), followed by two immunoglobulin (Ig)-like domains and a single transmembrane domain. The cytoplasmic domain of Trk receptors contains several tyrosine motifs (Huang and Reichardt, 2003). The major ligand binding site on Trk receptors is located in the region proximal to the Ig-... 

Steward, A., Adhya, S., Clarke, J. Sequence conservation in Ig-like domains The role of highly conserved proline residues in the fibronectin type III superfamily. J. Mol. Biol. 2002, 318, 935-40. 

Martin M, Romero X, de la Fuente MA, Tovar V, Zapater N, Esplugues E et al (2001) CD84 functions as a homophilic adhesion molecule and enhances IFN-gamma secretion adhesion is mediated by Ig-like domain 1. J Immunol (Balt) 167 3668-3676... 

The Ig-superfamily contains many proteins involved in immune recognition such as products of the MHC complex and accessory molecules [53]. In addition there are ten or more members associated mainly with nervous tissues in mature animals and several others in non-nervous tissue that are important factors in cell-cell and cell-substratum adhesion in non-immune cells. See [54] and [55] for detailed discussion of other aspects of Ig-superfamily glycoproteins. All of the cell adhesion glycoproteins in the family contain a variable number of Ig-like domains of about one hundred amino-acid residues, usually but not always defined within a pair of disulfide-bonded cysteine residues, and of the C2 type fold. In many cases the molecules contain variable numbers of another type of modular sequence known as the fibronectin type III repeat, sinee it was discovered in fibroneetin. In the following discussion, some principles of the structure and functions of this large family of cell adhesion molecules will be considered with particular emphasis on the interplay between different members in adhesion and modulation of adhesive interactions by carbohydrates. 

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