The immunoglobulin domain, also known as the immunoglobulin fold, is a type of protein domain that consists of a 2-layer sandwich of 7-9 antiparallel β-strands arranged in two β-sheets with a Greek key topology, consisting of 70-125 amino acids.
The backbone switches repeatedly between the two β-sheets. Typically, the pattern is (N-terminal β-hairpin in sheet 1)-(β-hairpin in sheet 2)-(β-strand in sheet 1)-(C-terminal β-hairpin in sheet 2). The cross-overs between sheets form an "X", so that the N- and C-terminal hairpins are facing each other. Every other residue in the β-strands that faces the interface between the two sheets is hydrophobic. Hydrophobic interactions at this interface, together with the highly conserved disulfide bond linking the cysteine residues on the B and F strands, stabilize the Ig domain.
There are several types of immunoglobulin domains; the most common are constant (IgC), intermediate and variable, IgV. The difference in the structure is shown in the schematic figure below. The constant IgC domain consists of seven β-strands. The loops connecting the β-strands in IgC are short, meaning most amino acid residues are part of the β-strands. The IgC domains are further divided into two subclasses: IgC1 (typical constant domain) and IgC2 (less common). The IgC1 β-sandwich consists of two sheets: the first sheet is formed by strands A, B, E, and D and the second sheet is formed by strands G, F, and C. In contrast, IgC2 lacks strand D but includes an additional strand, C’. IgC2 is found in T-cell surface antigens (CD2, CD4, CD80) and cell adhesion molecules (VCAM, ICAM). The loops connecting the β-strands in IgC are short, meaning most amino acids are part of the β-strands.
Variable immunoglobulin IgV domain consists of two β-sheets formed by strands ABDE and GFCC′C″. IgV domains are essential components of antibodies and T-cell receptors because they contain the antigen-binding sites, known as complementarity-determining regions (CDRs). The CDRs are formed by three variable loops, which are generally longer than the corresponding loops in IgC domains. Specifically, the loop between strands B and C constitutes CDR1, the loop between strands C′ and C″ forms CDR2, and the loop between strands F and G forms CDR3. Together, these loops mediate antigen recognition and binding by antibodies and T-cell receptors.
The immunoglobulin domain is found in numerous proteins of the immunoglobulin superfamily (IgSF), where it mediates molecular recognition, protein–protein interactions, and cell adhesion. Genome-wide analyses have identified the Ig domain as one of the most abundant protein structural motifs in humans. In addition to immunoglobulins (antibodies), the IgSF comprises more than 750 proteins, including major histocompatibility complex (MHC) molecules, T-cell receptors (TCRs), the co-receptors CD3, CD4, and CD8, cytokine and growth factor receptors, natural killer (NK) cell receptors, and numerous other regulators of immune responses. Although the majority of IgSF proteins are membrane-bound, some are soluble and function either within the cytoplasm or in the extracellular space.
Protein chains may contain only a single immunoglobulin domain, as in β₂-microglobulin; they may contain one Ig domain together with several other domains, as in major histocompatibility complex (MHC) proteins; or they may consist of multiple Ig domains, as in antibodies, where each chain forms an N-terminal variable domain and two constant Ig domains (IgC1). The largest known human protein, titin (34,350 amino acids), contains 152 Ig domains in addition to hundreds of domains with other structural folds.
Members of the immunoglobulin superfamily are found in hundreds of proteins of different functions. Examples include antibodies, the giant muscle kinase titin, and receptor tyrosine kinases. Immunoglobulin-like domains may be involved in protein–protein and protein–ligand interactions.
Examples
Human genes encoding proteins containing the immunoglobulin domain include:
A1BG ACAM ADAMTSL1 ADAMTSL3 AGER ALCAM AMIGO1 AMIGO2 AXL BCAM BOC BSG BTLA C10orf72 C20orf102 CADM1 CADM3 CD200 CD22 CD276 CD33 CD4 CDON CEACAM1 CEACAM16 CEACAM20 CEACAM21 CEACAM5 CEACAM6 CEACAM8 CHL1 CILP CNTFR CNTN1 CNTN2 CNTN3 CNTN4 CNTN5 CNTN6 CSF1R DSCAM DSCAML1 EMB F11R FAIM3 FCAR FCER1A FCGR1A FCGR2A FCGR2B FCGR2C FCGR3A FCGR3B FCRH1 FCRH3 FCRH4 FCRL1 FCRL2 FCRL3 FCRL4 FCRL5 FCRL6 FCRLA FGFR1 FGFR2 FGFR3 FGFR4 FGFRL1 FLT1 FLT3 FLT4 FSTL4 FSTL5 GP6 GPA33 GPR116 GPR125 HEPACAM HLA-DMA HLA-DMB HLA-DQB HLA-DQB1 HMCN1 HNT HSPG2 HYST2477 ICAM3 ICAM5 IGHA1 IGHD IGHE IGSF10 IGSF11 IGSF2 IGSF21 IGSF3 IGSF9 IL11RA IL1R1 IL1R2 IL1RAPL1 IL1RAPL2 IL1RL1 IL1RL2 IL6R JAM2 JAM3 KIR-123FM KIR2DL1 KIR2DL2 KIR2DL3 KIR2DL4 KIR2DL5A KIR2DL5B KIR2DLX KIR2DS1 KIR2DS2 KIR2DS3 KIR2DS4 KIR2DS5 KIR3DL1 KIR3DL2 KIR3DL3 KIR3DS1 KIT L1CAM LAG3 LILRA1 LILRA2 LILRA3 LILRA4 LILRA5 LILRA6 LILRB1 LILRB2 LILRB3 LILRB4 LILRB5 LILRP2 LRIG1 LRIG2 LRIG3 LRIT1 LRRC4 LSAMP MAG MALT1 MCAM MDGA1 MDGA2 MERTK MFAP3 MIR MIR MXRA5 MYBPC3 MYOM1 MYOM3 NCA NCAM1 NCAM2 NEGR1 NEO1 NFASC NOPE NPHS1 NPTN NRCAM NRG1 NT NTRK3 OBSCN OBSL1 OPCML PAPLN PDGFRA PDGFRB PDGFRL PECAM1 PRODH2 PSG1 PSG10 PSG11 PSG11s' PSG2 PSG3 PSG4 PSG5 PSG6 PSG7 PSG8 PSG9 PTGFRN PTK7 PTPRD PTPRK PTPRM PTPRS PTPsigma PUNC PVR PVRL1 PVRL2 PVRL4 RAGE SCN1B SDK1 SDK2 SEMA3A SEMA3B SEMA3E SEMA3F SEMA3G SEMA4D SIGLEC1 SIGLEC10 SIGLEC11 SIGLEC12 SIGLEC14 SIGLEC6 SIGLEC7 SIGLEC8 SIRPG THY1 TIE1 TMIGD1 TMIGD2 TTN TYRO3 UNC5D VCAM1 VSIG1 VSIG2 VSIG4 hEMMPRIN kir3d
See also Immunoglobulin superfamily
References
External links SCOP listing of immunoglobulin domains of known structure