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Immunoglobulin M AI simulator
(@Immunoglobulin M_simulator)
Hub AI
Immunoglobulin M AI simulator
(@Immunoglobulin M_simulator)
Immunoglobulin M
Immunoglobulin M (IgM) is the largest of several isotypes of antibodies (also known as immunoglobulin) that are produced by vertebrates. IgM is the first antibody to appear in the response to initial exposure to an antigen; causing it to also be called an acute phase antibody. In humans and other mammals that have been studied, plasmablasts in the spleen are the main source of specific IgM production.
In 1937, an antibody was observed in horses hyper-immunized with pneumococcus polysaccharide that was much larger in size than the typical rabbit γ-globulin, with a molecular weight of 990,000 daltons. In accordance with its larger size, the new antibody was originally referred to as γ-macroglobulin, and subsequently termed IgM—M for “macro”. The V domains of normal immunoglobulin are highly heterogeneous, reflecting their role in protecting against the great variety of infectious microbes, and this heterogeneity impeded detailed structural analysis of IgM. Two sources of homogeneous IgM were subsequently discovered. First, the high molecular weight protein produced by some multiple myeloma patients was recognized to be a tumor-produced γ-macroglobulin, and because the tumor is a clone, the IgM it produces is homogeneous. In the 1960s, methods were developed for inducing immunoglobulin-producing tumors (plasmacytomas) in mice, thus providing a source of homogeneous immunoglobulins of various isotypes, including IgM (reviewed in). More recently, the expression of engineered immunoglobulin genes in tissue culture can be used to produce IgM with specific alterations and thus to identify the molecular requirements for features of interest.[citation needed]
Immunoglobulins are composed of light chains and heavy chains. The light chain (λ or κ) is a protein of ~220 amino acids, composed of a variable domain, VL (a segment of approximately 110 amino acids), and a constant domain, CL (also approximately 110 amino acids long). The μ heavy chain of IgM is a protein of ~576 amino acids, includes a variable domain (VH ~110 amino acids), four distinct constant region domains (Cμ1, Cμ2, Cμ3, Cμ4, each ~110 amino acids) and a "tailpiece" of ~20 amino acids. The μ heavy chain bears oligosaccharides at five asparagine residues. The oligosaccharides on mouse and human IgM have been partially characterized by a variety of techniques, including NMR, lectin binding, various chromatographic systems, and enzymatic sensitivity (reviewed in). The structure of the oligosaccharides at each site varies in detail, and the predominant oligosaccharides—biantennary, triantennary, and high mannose—differ among the sites.[citation needed]
The multimeric structure of IgM is shown schematically in Figure 1. Figure 1A shows the "heterodimer" composed of one light chain, denoted L, and one heavy chain, denoted μ. The heavy and light chains are held together both by disulfide bonds (depicted as red triangles) and by non-covalent interactions.
Figure 1B shows two μL units linked by a disulfide bond in the Cμ2 domains; this (μL)2 structure is often referred to as the IgM "monomer", as it is analogous in some ways to the structure of immunoglobulin G (IgG).
On the basis of its sedimentation velocity and appearance in electron micrographs, it was inferred that IgM usually occurs as a "pentamer", i.e., a polymer composed of five “monomers” [(μL)2]5, and was originally depicted by the models in Figures 1C and 1D, with disulfide bonds between the Cμ3 domains and between the tail pieces. Also shown is that pentameric IgM includes a third protein, the J chain. J chain (J for joining) was discovered as a covalently bonded component of polymeric IgA and IgM. The J chain is a small (~137 amino acids), acidic protein. As shown, the J chain joins two μ chains via disulfide bonds involving cysteines in the tailpieces.
It was initially expected that the J chain would be important for forming the polymeric immunoglobulins, and indeed polymerization of IgA depends strongly (but not absolutely) on the J chain. In contrast, polymeric IgM forms efficiently in the absence of the J chain.
The predominant form of human and mouse IgM is the pentamer. By way of comparison, the structure of IgM from frogs (Xenopus) is predominantly hexameric, IgM from bony fish is predominantly tetrameric, and IgM from cartilaginous fish (mainly sharks) is predominantly pentameric. Although the pentameric form predominates in mice and humans, the hexameric form has also been observed. Subsequent studies using recombinant DNA expression systems indicated that a hexamer is a major form of mouse IgM when the IgM is produced under conditions where the incorporation of the J chain is prevented, either by producing IgM in cells that lack the J chain or by producing IgM with a μ heavy chain that lacks the cysteine in the tailpiece. In summary, hexameric IgM never contains the J chain; pentameric IgM can be formed so as to include or not include the J chain.
Immunoglobulin M
Immunoglobulin M (IgM) is the largest of several isotypes of antibodies (also known as immunoglobulin) that are produced by vertebrates. IgM is the first antibody to appear in the response to initial exposure to an antigen; causing it to also be called an acute phase antibody. In humans and other mammals that have been studied, plasmablasts in the spleen are the main source of specific IgM production.
In 1937, an antibody was observed in horses hyper-immunized with pneumococcus polysaccharide that was much larger in size than the typical rabbit γ-globulin, with a molecular weight of 990,000 daltons. In accordance with its larger size, the new antibody was originally referred to as γ-macroglobulin, and subsequently termed IgM—M for “macro”. The V domains of normal immunoglobulin are highly heterogeneous, reflecting their role in protecting against the great variety of infectious microbes, and this heterogeneity impeded detailed structural analysis of IgM. Two sources of homogeneous IgM were subsequently discovered. First, the high molecular weight protein produced by some multiple myeloma patients was recognized to be a tumor-produced γ-macroglobulin, and because the tumor is a clone, the IgM it produces is homogeneous. In the 1960s, methods were developed for inducing immunoglobulin-producing tumors (plasmacytomas) in mice, thus providing a source of homogeneous immunoglobulins of various isotypes, including IgM (reviewed in). More recently, the expression of engineered immunoglobulin genes in tissue culture can be used to produce IgM with specific alterations and thus to identify the molecular requirements for features of interest.[citation needed]
Immunoglobulins are composed of light chains and heavy chains. The light chain (λ or κ) is a protein of ~220 amino acids, composed of a variable domain, VL (a segment of approximately 110 amino acids), and a constant domain, CL (also approximately 110 amino acids long). The μ heavy chain of IgM is a protein of ~576 amino acids, includes a variable domain (VH ~110 amino acids), four distinct constant region domains (Cμ1, Cμ2, Cμ3, Cμ4, each ~110 amino acids) and a "tailpiece" of ~20 amino acids. The μ heavy chain bears oligosaccharides at five asparagine residues. The oligosaccharides on mouse and human IgM have been partially characterized by a variety of techniques, including NMR, lectin binding, various chromatographic systems, and enzymatic sensitivity (reviewed in). The structure of the oligosaccharides at each site varies in detail, and the predominant oligosaccharides—biantennary, triantennary, and high mannose—differ among the sites.[citation needed]
The multimeric structure of IgM is shown schematically in Figure 1. Figure 1A shows the "heterodimer" composed of one light chain, denoted L, and one heavy chain, denoted μ. The heavy and light chains are held together both by disulfide bonds (depicted as red triangles) and by non-covalent interactions.
Figure 1B shows two μL units linked by a disulfide bond in the Cμ2 domains; this (μL)2 structure is often referred to as the IgM "monomer", as it is analogous in some ways to the structure of immunoglobulin G (IgG).
On the basis of its sedimentation velocity and appearance in electron micrographs, it was inferred that IgM usually occurs as a "pentamer", i.e., a polymer composed of five “monomers” [(μL)2]5, and was originally depicted by the models in Figures 1C and 1D, with disulfide bonds between the Cμ3 domains and between the tail pieces. Also shown is that pentameric IgM includes a third protein, the J chain. J chain (J for joining) was discovered as a covalently bonded component of polymeric IgA and IgM. The J chain is a small (~137 amino acids), acidic protein. As shown, the J chain joins two μ chains via disulfide bonds involving cysteines in the tailpieces.
It was initially expected that the J chain would be important for forming the polymeric immunoglobulins, and indeed polymerization of IgA depends strongly (but not absolutely) on the J chain. In contrast, polymeric IgM forms efficiently in the absence of the J chain.
The predominant form of human and mouse IgM is the pentamer. By way of comparison, the structure of IgM from frogs (Xenopus) is predominantly hexameric, IgM from bony fish is predominantly tetrameric, and IgM from cartilaginous fish (mainly sharks) is predominantly pentameric. Although the pentameric form predominates in mice and humans, the hexameric form has also been observed. Subsequent studies using recombinant DNA expression systems indicated that a hexamer is a major form of mouse IgM when the IgM is produced under conditions where the incorporation of the J chain is prevented, either by producing IgM in cells that lack the J chain or by producing IgM with a μ heavy chain that lacks the cysteine in the tailpiece. In summary, hexameric IgM never contains the J chain; pentameric IgM can be formed so as to include or not include the J chain.
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