Immunoglobulin superfamily

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Immunoglobulin superfamily
PDB 1a2y EBI.jpg
Antibody in complex with hen egg white lysozyme. [1]
Identifiers
SymbolIgSF
Pfam PF00047
Pfam clan CL0011
InterPro IPR013151
PROSITE PS50835
SCOP2 1tlk / SCOPe / SUPFAM
OPM superfamily 193
OPM protein 3bib
CDD cd00096
Membranome 2
Immunoglobulin-like (ligands)
Identifiers
SymbolIg protein ligands
Membranome 64
Immunoglobulin-like adhesion molecules
Identifiers
SymbolIgSF CAM
Membranome 110

The immunoglobulin superfamily (IgSF) is a large protein superfamily of cell surface and soluble proteins that are involved in the recognition, binding, or adhesion processes of cells. Molecules are categorized as members of this superfamily based on shared structural features with immunoglobulins (also known as antibodies); they all possess a domain known as an immunoglobulin domain or fold. Members of the IgSF include cell surface antigen receptors, co-receptors and co-stimulatory molecules of the immune system, molecules involved in antigen presentation to lymphocytes, cell adhesion molecules, certain cytokine receptors and intracellular muscle proteins. They are commonly associated with roles in the immune system. Otherwise, the sperm-specific protein IZUMO1, a member of the immunoglobulin superfamily, has also been identified as the only sperm membrane protein essential for sperm-egg fusion.

Contents

Immunoglobulin domains

Proteins of the IgSF possess a structural domain known as an immunoglobulin (Ig) domain. Ig domains are named after the immunoglobulin molecules. They contain about 70-110 amino acids and are categorized according to their size and function. [2] Ig-domains possess a characteristic Ig-fold, which has a sandwich-like structure formed by two sheets of antiparallel beta strands. Interactions between hydrophobic amino acids on the inner side of the sandwich and highly conserved disulfide bonds formed between cysteine residues in the B and F strands, stabilize the Ig-fold.[ citation needed ]

Classification

The Ig like domains can be classified as IgV, IgC1, IgC2, or IgI. [3]

Most Ig domains are either variable (IgV) or constant (IgC).

Members

The Ig domain was reported to be the most populous family of proteins in the human genome with 765 members identified. [5] Members of the family can be found even in the bodies of animals with a simple physiological structure such as poriferan sponges. They have also been found in bacteria, where their presence is likely to be due to divergence from a shared ancestor of eukaryotic immunoglobulin superfamily domains. [6]

Members of the immunoglobulin superfamily
Molecule function/categoryExamplesDescription
Antigen receptorsAntigen receptors found on the surface of T and B lymphocytes in all jawed vertebrates belong to the IgSF. Immunoglobulin molecules (the antigen receptors of B cells) are the founding members of the IgSF. In humans, there are five distinct types of immunoglobulin molecule all containing a heavy chain with four Ig domains and a light chain with two Ig domains. The antigen receptor of T cells is the T-cell receptor (TCR), which is composed of two chains, either the TCR-alpha and -beta chains, or the TCR-delta and gamma chains. All TCR chains contain two Ig domains in the extracellular portion; one IgV domain at the N-terminus and one IgC1 domain adjacent to the cell membrane.
Antigen presenting moleculesThe ligands for TCRs are major histocompatibility complex (MHC) proteins. These come in two forms; MHC class I forms a dimer with a molecule called beta-2 microglobulin (β2M) and interacts with the TCR on cytotoxic T cells and MHC class II has two chains (alpha and beta) that interact with the TCR on helper T cells. MHC class I, MHC class II and β2M molecules all possess Ig domains and are therefore also members of the IgSF.
Co-receptors Co-receptors and accessory molecules: Other molecules on the surfaces of T cells also interact with MHC molecules during TCR engagement. These are known as co-receptors. In lymphocyte populations, the co-receptor CD4 is found on helper T cells and the co-receptor CD8 is found on cytotoxic T cells. CD4 has four Ig domains in its extracellular portion and functions as a monomer. CD8, in contrast, functions as a dimer with either two identical alpha chains or, more typically, with an alpha and beta chain. CD8-alpha and CD8-beta each has one extracellular IgV domain in its extracellular portion. A co-receptor complex is also used by the BCR, including CD19, an IgSF molecule with two IgC2-domains.
Antigen receptor accessory moleculesA further molecule is found on the surface of T cells that is also involved in signaling from the TCR. CD3 is a molecule that helps to transmit a signal from the TCR following its interaction with MHC molecules. Three different chains make up CD3 in humans, the gamma chain, delta chain and epsilon chain, all of which are IgSF molecules with a single Ig domain.

Similar to the situation with T cells, B cells also have cell surface co-receptors and accessory molecules that assist with cell activation by the B Cell Receptor (BCR)/immunoglobulin. Two chains are used or signaling, CD79a and CD79b that both possess a single Ig domain.

Co-stimulatory or inhibitory moleculesCo-stimulatory or inhibitory molecules: Co-stimulatory and inhibitory signaling receptors and ligands control the activation, expansion and effector functions of cells. One major group of IgSF co-stimulatory receptors are molecules of the CD28 family; CD28, CTLA-4, program death-1 (PD-1), the B- and T-lymphocyte attenuator (BTLA, CD272), and the inducible T-cell co-stimulator (ICOS, CD278); [7] and their IgSF ligands belong to the B7 family; CD80 (B7-1), CD86 (B7-2), ICOS ligand, PD-L1 (B7-H1), PD-L2 (B7-DC), B7-H3, and B7-H4 (B7x/B7-S1). [8]
Receptors on Natural killer cells
Receptors on Leukocytes
IgSF CAMs
  • NCAMs
  • ICAM-1
  • CD2 subset
  • Type IIa and Type IIb RPTPs, described in Receptor tyrosine kinases/phosphatases subsection below
Cytokine receptors
Growth factor receptors
Receptor tyrosine kinases/phosphatases
Ig binding receptors
Cytoskeleton
Others

Related Research Articles

Antibody Protein(s) forming a major part of an organisms immune system

An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the pathogen, called an antigen. Each tip of the "Y" of an antibody contains a paratope that is specific for one particular epitope on an antigen, allowing these two structures to bind together with precision. Using this binding mechanism, an antibody can tag a microbe or an infected cell for attack by other parts of the immune system, or can neutralize it directly.

Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the binding of cells with other cells or with the extracellular matrix (ECM), in a process called cell adhesion. In essence, CAMs help cells stick to each other and to their surroundings. CAMs are crucial components in maintaining tissue structure and function. In fully developed animals, these molecules play an integral role in generating force and movement and consequently ensuring that organs are able to execute their functions normally. In addition to serving as "molecular glue", CAMs play important roles in the cellular mechanisms of growth, contact inhibition, and apoptosis. Aberrant expression of CAMs may result in a wide range of pathologies, ranging from frostbite to cancer.

CD8 is a transmembrane glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). Along with the TCR, the CD8 co-receptor plays a role in T cell signaling and aiding with cytotoxic T cell-antigen interactions.

CD31

Platelet endothelial cell adhesion molecule (PECAM-1) also known as cluster of differentiation 31 (CD31) is a protein that in humans is encoded by the PECAM1 gene found on chromosome17q23.3. PECAM-1 plays a key role in removing aged neutrophils from the body.

CD28

CD28 is one of the proteins expressed on T cells that provide co-stimulatory signals required for T cell activation and survival. T cell stimulation through CD28 in addition to the T-cell receptor (TCR) can provide a potent signal for the production of various interleukins.

Complementarity-determining region Part of the variable chains in immunoglobulins and T cell receptors

Complementarity-determining regions (CDRs) are part of the variable chains in immunoglobulins (antibodies) and T cell receptors, generated by B-cells and T-cells respectively, where these molecules bind to their specific antigen. A set of CDRs constitutes a paratope. As the most variable parts of the molecules, CDRs are crucial to the diversity of antigen specificities generated by lymphocytes.

Killer-cell immunoglobulin-like receptors (KIRs), are a family of type I transmembrane glycoproteins expressed on the plasma membrane of natural killer (NK) cells and a minority of T cells. At least 15 genes and 2 pseudogenes encoding KIR map in a 150-kb region of the leukocyte receptor complex (LRC) on human chromosome 19q13.4.

An immunoreceptor tyrosine-based inhibitory motif (ITIM), is a conserved sequence of amino acids that is found intracellularly in the cytoplasmic domains of many inhibitory receptors of the non-catalytic tyrosine-phosphorylated receptor family found on immune cells. These immune cells include T cells, B cells, NK cells, dendritic cells, macrophages and mast cells. ITIMs have similar structures of S/I/V/LxYxxI/V/L, where x is any amino acid, Y is a tyrosine residue that can be phosphorylated, S is the amino acide Serine, I is the amino acid Isoleucine, and V is the amino acid Valine. ITIMs recruit SH2 domain-containing phosphatases, which inhibit cellular activation. ITIM-containing receptors often serve to target Immunoreceptor tyrosine-based activation motif(ITAM)-containing receptors, resulting in an innate inhibition mechanism within cells. ITIM bearing receptors have important role in regulation of immune system allowing negative regulation at different levels of the immune response.

Basigin Mammalian protein found in Homo sapiens

Basigin (BSG) also known as extracellular matrix metalloproteinase inducer (EMMPRIN) or cluster of differentiation 147 (CD147) is a protein that in humans is encoded by the BSG gene. This protein is a determinant for the Ok blood group system. There are three known antigens in the Ok system; the most common being Oka, OK2 and OK3. Basigin has been shown to be an essential receptor on red blood cells for the human malaria parasite, Plasmodium falciparum.

LILRB1 Protein-coding gene in the species Homo sapiens

Leukocyte immunoglobulin-like receptor subfamily B member 1 is a protein that in humans is encoded by the LILRB1 gene.

F11 receptor

Junctional adhesion molecule A is a protein that in humans is encoded by the F11R gene. It has also been designated as CD321.

Poliovirus receptor-related 1

Poliovirus receptor-related 1 (PVRL1), also known as nectin-1 and CD111 (formerly herpesvirus entry mediator C, HVEC) is a human protein of the immunoglobulin superfamily (IgSF), also considered a member of the nectins. It is a membrane protein with three extracellular immunoglobulin domains, a single transmembrane helix and a cytoplasmic tail. The protein can mediate Ca2+-independent cellular adhesion further characterizing it as IgSF cell adhesion molecule (IgSF CAM).

CD48 Mammalian protein found in Homo sapiens

CD48 antigen also known as B-lymphocyte activation marker (BLAST-1) or signaling lymphocytic activation molecule 2 (SLAMF2) is a protein that in humans is encoded by the CD48 gene.

CD84 Mammalian protein found in Homo sapiens

CD84 is a human protein encoded by the CD84 gene.

Basal cell adhesion molecule Protein-coding gene in the species Homo sapiens

Basal cell adhesion molecule, also known as Lutheran antigen, is a plasma membrane glycoprotein that in humans is encoded by the BCAM gene. BCAM has also recently been designated CD239.

LILRB4 Protein-coding gene in the species Homo sapiens

Leukocyte immunoglobulin-like receptor subfamily B member 4 is a protein that in humans is encoded by the LILRB4 gene.

BTLA

B- and T-lymphocyte attenuator or BTLA is a protein that belongs to the CD28 immunoglobulin superfamily (IgSF) which is encoded by the BTLA gene located on the 3rd human chromosome. BTLA was first discovered in 2003 as an inhibitor of Th1 expansion and it became the 3rd member of the CD28 IgSF. However, its discovered ligand herpes virus entry mediator or HVEM belongs to the tumor necrosis factor receptor superfamily (TNFRSF). This finding was surprising because until the discovery of HVEM it was believed that receptors and ligands always belong to the same family.

LILRA3 Protein-coding gene in the species Homo sapiens

Leukocyte immunoglobulin-like receptor subfamily A member 3 (LILR-A3) also known as CD85 antigen-like family member E (CD85e), immunoglobulin-like transcript 6 (ILT-6), and leukocyte immunoglobulin-like receptor 4 (LIR-4) is a protein that in humans is encoded by the LILRA3 gene located within the leukocyte receptor complex on chromosome 19q13.4. Unlike many of its family, LILRA3 lacks a transmembrane domain. The function of LILRA3 is currently unknown; however, it is highly homologous to other LILR genes, and can bind human leukocyte antigen (HLA) class I. Therefore, if secreted, the LILRA3 might impair interactions of membrane-bound LILRs with their HLA ligands, thus modulating immune reactions and influencing susceptibility to disease.

The basic structure of immunoglobulin (Ig) molecules is a tetramer of two light chains and two heavy chains linked by disulphide bonds. There are two types of light chains: kappa and lambda, each composed of a constant domain (CL) and a variable domain (VL). There are five types of heavy chains: alpha, delta, epsilon, gamma and mu, all consisting of a variable domain (VH) and three or four constant domains. Ig molecules are highly modular proteins, in which the variable and constant domains have clear, conserved sequence patterns. The domains in Ig and Ig-like molecules are grouped into four types: V-set, C1-set, C2-set and I-set. Structural studies have shown that these domains share a common core Greek-key beta-sandwich structure, with the types differing in the number of strands in the beta-sheets as well as in their sequence patterns.

CD96 Protein-coding gene in the species Homo sapiens

CD96 or Tactile is a protein that in humans is encoded by the CD96 gene. CD96 is a receptor protein which is expressed on T cells and NK cells and shares sequence similarity with CD226. The protein encoded by this gene belongs to the immunoglobulin superfamily. It is a type I membrane protein. The protein may play a role in the adhesion of activated T and NK cells to their target cells during the late phase of the immune response. It may also function in antigen presentation. Alternative splicing occurs at this locus and two transcript variants encoding distinct isoforms have been identified. CD96 is a transmembrane glycoprotein that has three extracellular immunoglobulin-like domains and is expressed by all resting human and mouse NK cells. CD96 main ligand is CD155. CD 96 has approximately 20% homology with CD226 and competed for binding to CD155 with CD226.

References

  1. ↑ Dall'Acqua W, Goldman ER, Lin W, Teng C, Tsuchiya D, Li H, Ysern X, Braden BC, Li Y, Smith-Gill SJ, Mariuzza RA (June 1998). "A mutational analysis of binding interactions in an antigen-antibody protein-protein complex". Biochemistry. 37 (22): 7981–91. doi:10.1021/bi980148j. PMID   9609690.
  2. ↑ Barclay AN (August 2003). "Membrane proteins with immunoglobulin-like domains--a master superfamily of interaction molecules". Seminars in Immunology. 15 (4): 215–23. doi:10.1016/S1044-5323(03)00047-2. PMID   14690046.
  3. ↑ B. D. Gomperts; Ijsbrand M. Kramer; Peter E. R. Tatham (1 July 2009). Signal transduction. Academic Press. pp. 378–. ISBN   978-0-12-369441-6 . Retrieved 28 November 2010.
  4. ↑ Harpaz Y, Chothia C (May 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 (4): 528–39. doi:10.1006/jmbi.1994.1312. PMID   8176743.
  5. ↑ Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, et al. (February 2001). "Initial sequencing and analysis of the human genome" (PDF). Nature. 409 (6822): 860–921. doi: 10.1038/35057062 . PMID   11237011.
  6. ↑ Bateman A, Eddy SR, Chothia C (September 1996). "Members of the immunoglobulin superfamily in bacteria". Protein Science. 5 (9): 1939–41. doi:10.1002/pro.5560050923. PMC   2143528 . PMID   8880921.
  7. ↑ Peggs KS, Allison JP (September 2005). "Co-stimulatory pathways in lymphocyte regulation: the immunoglobulin superfamily". British Journal of Haematology. 130 (6): 809–24. doi: 10.1111/j.1365-2141.2005.05627.x . PMID   16156851.
  8. ↑ Greenwald RJ, Freeman GJ, Sharpe AH (2005). "The B7 family revisited". Annual Review of Immunology. 23: 515–48. doi:10.1146/annurev.immunol.23.021704.115611. PMID   15771580.
  9. ↑ Boles KS, Stepp SE, Bennett M, Kumar V, Mathew PA (June 2001). "2B4 (CD244) and CS1: novel members of the CD2 subset of the immunoglobulin superfamily molecules expressed on natural killer cells and other leukocytes". Immunological Reviews. 181: 234–49. doi:10.1034/j.1600-065X.2001.1810120.x. PMID   11513145. S2CID   21801197.
  10. ↑ Fraser CC, Howie D, Morra M, Qiu Y, Murphy C, Shen Q, Gutierrez-Ramos JC, Coyle A, Kingsbury GA, Terhorst C (February 2002). "Identification and characterization of SF2000 and SF2001, two new members of the immune receptor SLAM/CD2 family". Immunogenetics. 53 (10–11): 843–50. doi:10.1007/s00251-001-0415-7. PMID   11862385. S2CID   10257502.
  11. ↑ Tangye SG, Nichols KE, Hare NJ, van de Weerdt BC (September 2003). "Functional requirements for interactions between CD84 and Src homology 2 domain-containing proteins and their contribution to human T cell activation". Journal of Immunology. 171 (5): 2485–95. doi: 10.4049/jimmunol.171.5.2485 . PMID   12928397.
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