As implied by its name, the Ig domain was first recognized in antibodies.[1] The human genome project has identified the Ig superfamily (IgSF) as the largest superfamily in the human genome, due to its extensive usage in the immune system.[2] Although Ig-like domains also exist in a few intracellular proteins, they are found predominately in the extracellular space and are the most abundant structural unit found in cell surface receptors, serving key recognition functions in both the immune and nervous systems. Along with a handful of other modular domains such as fibronectin type III domains and epidermal growth factor (EGF) domains, they form modular structures of most receptor molecules on the cell surface.

An Ig domain is composed of approximately 100 residues, folding into two β-sheets packing face-to-face, forming a β-barrel. This distinctively folded structure is commonly known as the Ig fold (Fig. 1A). An intact IgG antibody consists of two heavy chains and two light chains. Each heavy chain contains four Ig domains, one “variable” domain and three “constant” domains, and each light chain contains two Ig domains, one variable and one constant. The variable and constant Ig domains differ somewhat in structure and are correspondingly classified as V-set and C-set Ig folds. A V-set Ig domain has β-strands A, B, E, and D on one sheet and A′, G, F, C, C′ and C″ strands on the other (see Fig. 1A), whereas a C-set Ig domain lacks A′, C′ and C″ strands on either edge (Fig. 1B). In both, the two sheets are linked together by a conserved disulfide bond between the B and F strands (reviewed in Williams et al.[3]). Within variable domains, hypervariable sequences are found in three connecting loops at one end of the domain. These loops are termed complementarity determining regions (CDRs) (see Fig. 1A). In the intact antibody, the CDRs of the heavy and light chains combine to make up the antigen-binding site. Fig. 2A depicts how the CDRs of a human immunodeficiency virus (HIV)-neutralizing antibody form an antigen-binding pocket that recognizes an antigenic peptide from an HIV surface protein.[4]

Fig1. IMMUNOGLOBULIN (IG) DOMAIN ARCHITECTURE. (A) V-set Ig domain (PDB entry 3IDG). The complementarity determining regions (CDR) are colored red. (B) C-set Ig domain (PDB entry 3IDG). (C) I-set Ig domain, which can be described as a truncated V-set domain (PDB entry 2V5M). Intersheet disulfide bonds are highlighted orange. PDB, Protein Data Bank..

Fig2. (A) Structure of a human immunodeficiency virus–neutralizing antibody in complex with an antigenic peptide. Complementarity determining regions (CDRs) of the heavy and light chains are shown in red and magenta, respectively. Only the two variable domains of the antibody are shown (drawn from PDB entry 3IDG). (B) Cryoelectron microscopy structure of a complete T-cell receptor (TCR)-CD3 complex. The TCR’s α- and β-chains are shown in green and cyan, respectively, with their CDR loops colored red. The CD3ε chains are pink, CD3δ light blue, CD3γ yellow, and CD3ζ magenta. (C) Structure of an antigenic peptide bound to a major histocompatibility complex (MHC) molecule in complex with TCR (drawn from PDB entry 2CKB). The TCR is shown in a similar orientation and with the same coloring as in panel B. MHC heavy chain is in yellow and β2-microglobulin domain in orange. The peptide antigen is shown in magenta. PDB, Protein Data Bank.

A similar structural platform is used in cellular immunity by T-cell receptors (TCRs), which, distinct from antibodies, recognize an antigenic peptide along with the major histocompatibility complex (MHC) molecule that presents the peptide on surface of an infected or cancerous cell. The complete TCR is a membrane spanning complex with CD3 that contains a total of eight Ig domains—two in each of the TCR α- and β-chains, and one in each of the dimeric CD3γε and CD3δε subunits. The CD3ζζ subunit, which contains only transmembrane helices and cytoplasmic tails, completes the receptor. Recent advances in cryoelectron microscopy (cryo-EM) have allowed elucidation of the structure of the intact TCR-CD3 complex,[5] revealing an overall architecture in which the extracellular “bouquet” of Ig domains is arranged on “stems” of eight transmembrane helices (Fig. 2B). Within this complex the CDR3 loops of the TCR α and β variable domains play a key role in antigen recognition, whereas germline-encoded CDR1 and CDR2 loops of the TCR are responsible for contacting the polymorphic region of the MHC molecule, with CDR1 also taking part in peptide binding.[6,7] Fig. 2C illustrates a typical crystal structure of a TCR in complex with an antigenic peptide bound to the MHC molecule.

A number of variations on the Ig fold are found in other cell sur face receptors. These Ig-like domains include the topologically similar fibronectin type III domains and the domains of cadherins, both of which lack the disulfide bridge found in the canonical Ig domain. Further variations are found in modular cell surface receptors, which often have a V-set Ig-like domain at their N-terminus, positioned to extend from the plasma membrane for ligand-binding, serving a role analogous to antigen-recognition. By contrast, “I-set” Ig-like domains (see Fig. 1C) usually function as one of the building blocks lined up in tandem to present the ligand-binding V-set domain on the cell surface. This can be seen in many immune receptors such as CD2, CD58,[8] and CD4.[9] There are also many receptors that are exclusively composed of I-set domains, including immune receptor intercellular adhesion molecule-1 (ICAM-1)[10] and neuroreceptors NCAM[11] and Dscam.[12] Thus the I-set variant is the most abundant Ig-like domain and plays a critical biologic role in cell surface receptors.

References

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[1] Bork P, Holm L, Sander C. The immunoglobulin fold. Structural classification, sequence patterns and common core. J Mol Biol. 1994;242:309–320.

[2] Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human genome. Nature. 2001;409:860–921. https://doi. org/10.1038/35057062.

 [3] Williams AF, Davis SJ, He Q, Barclay AN. Structural diversity in domains of the immunoglobulin superfamily. Cold Spring Harb Symp Quant Biol. 1989;54(Pt 2):637–647.

[4] Zwick MB, Kiyomi Komori H, Stanfield RL, et al. The long third complementarity-determining region of the heavy chain is important in the activity of the broadly neutralizing anti-human immunodeficiency virus type 1 antibody 2F5. J Virol. 2004;78:3155–3161.

[5] Dong D, Zheng L, Lin J, et al. Structural basis of assembly of the human T cell receptor-CD3 complex. Nature. 2019;573:546–552. https://doi. org/10.1038/s41586-019-1537-0.

[6] Wang JH, Reinherz EL. The structural basis of αβ T-lineage immune recognition: TCR docking topologies, mechanotransduction, and co-receptor function. Immunol Rev. 2012;250:102–119. https://doi. org/10.1111/j.1600-065X.2012.01161.x.

 [7] Rudolph MG, Stanfield RL, Wilson IA. How TCRs bind MHCs, peptides, and coreceptors. Annu Rev Immunol. 2006;24:419–466.

[8] Wang J-H, Smolyar A, Tan K, et al. Structure of a heterophilic adhesion complex between human CD2 and CD58 (LFA-3) counter-receptors. Cell. 1999;97:791–803.

[9] Wu H, Kwong PD, Hendrickson WA. Dimeric association and segmental variability in the structure of human CD4. Nature. 1997;387:527–530.

[10] Yang Y, Chang-Duk J, Liu J-H, et al. Structural basis for dimerization of ICAM-1 on the cell surface. Mol Cell. 2004;14:269–276.

[11] Cunningham BA, Hemperly JJ, Murray BA, et al. Neural cell adhesion molecule: structure, immunoglobulin-like domains, cell surface modulation, and alternative RNA splicing. Science. 1987;236:799–806.

[12] Meijers R, Puettmann-Holgado R, Skiniotis G, et al. Structural basis of Dscam isoform specificity. Nature. 2007;449:487–491.

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Deficiencies of the Immune Response

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Complement Deficiencies and Pathogen Evasion

Complement Pathways

T Cells

Antibody Responses

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Immunoglobulin Classes

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