"Refers to apparent molecular weight on reduced SDS-PAGE. Note that primary function is not necessarily mediated by IgSF domain (for example. MHC-peptide-binding groove is formed by the non-lgSF domains of the MHC molecules).

"Refers to apparent molecular weight on reduced SDS-PAGE. Note that primary function is not necessarily mediated by IgSF domain (for example. MHC-peptide-binding groove is formed by the non-lgSF domains of the MHC molecules).

content. The minority of Ig-type domains which lack disulfide bonds (e.g. the first domain of CD2 and the third domain of CD4) usually have hydrophobic amino acids which point inward and contribute to the hydrophobic interior between the @ sheets. The exon-intron gene structure can also be indicative of IgSF membership in that each Ig-type domain is usually encoded by one exon. Exceptions to this arrangement include the first domain of CD4. IgSF members are generally spread throughout the

Figure 1 Schematic drawing of an immunoglobulin variable domain showing the characteristic 'immunoglobulin fold'. (Copyright by Jane S. Richardson, reproduced with permission.)

chromosomes, although some members are genetically linked together. For example CD90(Thy-l), CD-56(NCAM) and CD3e, y and 8 are all found on chromosome 11 at band position q23.

One commonly used approach for sequence comparisons with known members of the superfamily utilizes the Dayhoff ALIGN program which scores similarities between the candidate sequence and several sequences from accepted Ig gene superfamily members. The alignments used for such sequence comparisons need careful consideration, taking into account such factors as the 3 strand/loop organization and the repertoire of conserved amino acids. No residue is invariant in all Ig-related domains and the primary structure of the Ig-type domains can be very different. This is vividly illustrated by the Ig variable region genes where even proteins encoded by the same gene family are sometimes <20% similar. Three domain patterns have been identified in the Ig gene superfamily, namely the V-, CI- and C2-related domains. Each domain consists of two (3 sheets forming the characteristic sandwich structure of the Ig fold. The V domain structure has an additional loop which, in Ig, forms the second hypervariable region. The C2 type domain is more compact than the CM and V domains and although it shares with

CI the lack of the additional loop found in V domains it appears, overall, to have a relatively equidistant relationship to both V and CI domain types. Some IgSF members possess Ig-type domains which exhibit features that make them somewhat difficult to assign to any one of the previously defined groups.

Since the members of the Ig superfamily are mostly located in environments in which proteases are common, it has been suggested that selection for resistance to proteolysis may be the key factor in conservation of sequence pattern yielding a compact globular structure. Indeed, the transmembrane and cytoplasmic regions of the Ig gene superfamily members are extremely diverse. For example, Thy-1 lacks a cytoplasmic domain and utilizes a glycophospho-lipid membrane anchor, whereas the CSF-l receptor (CD 115) has a long cytoplasmic domain which exhibits tyrosine kinase activity.

Although molecules of the Ig superfamily have diverse biological roles, a common theme among them is that homophilic (e.g. CD56-CD56) or het-erophilic (e.g. CD2-CD58) interactions between domains on different polypeptide chains are involved in their function. This has led to the suggestion that the superfamily has evolved from a single cell surface domain that was capable of homophilic interaction between cells. The existence of Ig superfamily members (fasciclin, neuroglian and amalgam) in insects and perhaps even in bacteria suggests that diversification of the domain occurred early in evolution. Gene duplication and subsequent divergence would allow the development of multidomain structures with diverse functions. Extensive diversification in the superfamily probably allowed heterophilic recognition between related molecules, leading to the sophisticated interactions seen in vertebrate immune systems.

See also: Adhesion molecules; CD2; CD3; CD4; CD8; CD28; Domains, immunoglobulin-type; Embryonic antigens; Fc receptors; H2 class I; H2 class II; HLA class I; HLA class II; Immunoglobulin structure; Intercellular adhesion molecules: ICAM-1, ICAM-2 and ICAM-3; Interleukin 6 receptor; Lymphocyte function-associated antigen 3 (LFA-3); Macrophage colony stimulating factor (CSF-1); Secretory component (the polymeric Ig receptor); T cell receptor, evolution of; Antibody-antigen complexes, three-dimensional structures; Thy-1; Tumor antigens; Cell surface receptors and adhesion molecules, three-dimensional structures.

Further reading

Anderson P, Morimoto C, Breitmcyer JB and Schlossman

SF (1988) Regulatory interactions between members of the immunoglobulin superfamily. Immunology Today 9: 199-203.

Barclay AN, Brown MH, Law SKA, McKnight Af, Tom-linson M G and van der Merwe PA (1997) The Leucocyte Antigen FactsBook, 2nd edn. London: Academic-Press.

Bateman A, Eddy SR and Chothia C (1996) Members of the immunoglobulin superfamily in bacteria. Protein Science 5: 1939-1941.

Harpaz Y and Chothia C (1994) Many of the immunoglobulin superfamily domains in cell adhesion molecules and surface receptors belong to a new structural set which is close to that containing variable domains. Journal of Molecular Biology 238: 528-539.

Hunkapillar T and Hood L (1989) Diversity of the immunoglobulin gene superfamily. Advances in Immunology 44: 1-63.

Keim S, Schauer R and Crocker PR (1996) The siaioadhes-ins - a family of sialic acid-dependent cellular recognition molecules within the immunoglobulin super-family. Glycoconjugate Journal 13: 913-926.

Marchalonis JJ, Hohman VS, Kaymaz H, Schl├╝ter SF and Edmundson AB (1994) Cell surface recognition and the immunoglobulin superfamily. Annals of the New York Academy of Sciences 712: 20-33.

Williams AF and Barclay AN (1988) The immunoglobulin superfamily: Domains for cell surface recognition. Annual Review of Immunology 6: 381-405.

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