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An Exclusive Preview Excerpt: Structure, Function, and Production of Immunoglobulin M (IgM)

By: , Posted on: April 21, 2016

We are thrilled to announce that the Encyclopedia of Immunobiology will be publishing May 2016! This 5 volume set will provide the largest integrated source of immunological knowledge currently available. As a taster we have provided an exclusive preview excerpt taken from the article Structure, Function, and Production of Immunoglobulin M (IgM) which is included in the forthcoming 5-volume reference work.

IgM is the first antibody produced after initial antigen exposure. Its high avidity enables it to bind antigen effectively, even with relatively low affinity binding sites, and to mobilize other effector arms of the immune system, namely complement and various Fc receptors.

The study of IgM (originally denoted as ϒ-macroglobulin – M for ‘macro’) began with the report in 1937 by Heidelberger and Pedersen that horses hyperimmunized with pneumococcus polysaccharide produced antibody that was much larger than the typical rabbit ϒ-globulin (Heidelberger and Pedersen, 1937). Soon thereafter, Kabat estimated the molecular weight of ϒ-macroglobulin to be 990 000 Da (Kabat, 1939), and this estimate led Waldenström to suggest that ϒ-macroglobulin might be the normal analogue of the high molecular weight protein that he observed in the sera of patients afflicted with ‘myelomatosis’ (now denoted as macroglobulinemia) (Waldenström, 1943). This prescient, albeit casually expressed, proposal was correct, and the homogeneous proteins of Waldenström’s macroglobulinemias allowed detailed molecular analyses (reviewed in Metzger, 1970). Independently, methods were developed for inducing plasmacytomas in mice, thus also providing a source of homogeneous immunoglobulins of various isotypes (reviewed in Potter, 2007).

Structure of IgM

IgM structure is typically represented by simple twodimensional models like those shown in Figure 1. The role of IgM in the immune response is complex, in that IgM functions both directly in combating microbial infection and also has a regulatory role.

IgM is produced in all vertebrates that have been studied, from fish to human, but with substantial species–specific differences in polymeric structure and presumably in other details. As represented in Figure 1, the μ chain includes five domains (VH, Cm1, Cm2, Cm3, Cm4), each folded in the typical Ig manner.

immunoglobulin
Figure 1 Schematic model of IgM. (a) The mL heterodimer, sometimes called a halfmer, with variable (VH, VL) and constant region (Cμ1, Cμ2, Cμ3, Cμ4, tp; CL) domains. C337, C414, C575 that mediate disulfide bonds between m chains are shown as red arrowheads; the cysteine disulfide bond between C140 in the Cμ1 domain and C214 in the CL (kappa) domain is shown as a red double arrowhead (red diamond). (b) The IgM ‘monomer’ (μL)2. The C337–C337 disulfide bonds between Cμ2 domains are represented by a red double arrowhead. (c, d) Two models for J-chain-containing IgM pentamer that have appeared in various publications at various times. As in (b), the C337–C337 disulfide bonds between Cμ2 domains and the C575–C575 disulfide bonds between Cμ4tp domains are represented by a red double arrowhead. The C414–C414 disulfide bonds are represented by the long double-headed arrows between Cμ3 domains. The connectivity, i.e., disulfide bonding of the m chains is conveniently denoted like electrical connections. In (c) the C414–C414 and C575–C575 disulfide bonds join μ chains in parallel, i.e., C414–C414 and C575–C575 join the same μ chains, and these disulfide bonds join μ chains in series with the C337–C337 bonds. In (d) C337–C337 and C575–C575 join μ chains in parallel and join m chains in series with C414–C414.

Although most textbooks depict IgM as in Figure 1, these models omit several important structural features:

  1. The figure shows IgM as a ‘pentamer’ composed of five ‘monomer’ subunits, where each monomer is an analogue of IgG, i.e., where each subunit is composed of two heterodimers, each including a μ-heavy chain and a light (k or l) chain. As illustrated, the two μ chains of the monomer are linked by a disulfide bond in the Cμ2 domains, which are thus considered to be analogous to the ϒ hinge. However, as described in section Hexameric and Pentameric IgM (available in the article Structure, Function, and Production of Immunoglobulin M (IgM) in the forthcoming Encyclopedia of Immunobiology), IgM also polymerizes as a ‘hexamer,’ which differs from the pentamer in several ways.
  2. Pentameric IgM is depicted in Figure 1 with one J chain. However, pentameric IgM can assemble in the absence of J chains, and hexameric IgM never contains J chain. The actual stoichiometry of J chain in pentameric IgM is uncertain.
  3. The models presume that each μ chain is linked by disulfide bonds to only two other μ chains. However, the connectivity of the μ chains in polymeric IgM is variable, and individual μ chains can apparently be disulfide bonded to three other m chains (section Inter-μ-Chain Disulfide Bonding, will be available in the article Structure, Function, and Production of Immunoglobulin M (IgM) in the forthcoming Encyclopedia of Immunobiology).
  4. In the common two-dimensional models, the subunits are presumed to lie in a planar ring. However, section Tertiary and Quaternary Structure of the μ Constant Region (will be available in the article Structure, Function, and Production of Immunoglobulin M (IgM) in the forthcoming Encyclopedia of Immunobiology) describes new information on the quaternary arrangement within the polymer.

encylopedia of immunology

Look out for the Encyclopedia of Immunobiology publishing May 2016, both in print and on ScienceDirect! A one-stop go-to reference, this encyclopedia will be ideal for students and professionals alike, providing relevant topics to those working on experimental and clinical immunology, microbiology, biochemistry, genetics, veterinary science, physiology, and hematology.

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