Sandbox Reserved 1771

This Sandbox is Reserved from February 27 through August 31, 2023 for use in the course CH462 Biochemistry II taught by R. Jeremy Johnson at the Butler University, Indianapolis, USA. This reservation includes Sandbox Reserved 1765 through Sandbox Reserved 1795.

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IgM B-cell Receptor

Introduction

B-cells play an important role of the human immune system and can be found circulating throughout the body. On the surface of B-cells, membrane bound B-cell receptors(BCRs) can be found. These complex proteins are made up of membrane bound immunoglobulins (mIg). There are several different types of BCRs, namely IgG, IgA, IgM, IgE, or IgD. Each specific BCR has important functions for different diseases, but the IgM BCR in particular is most interesting. The BCR consists mainly of three domains: extracellular, transmembrane, and intracellular. While the extracellular region makes up most of the protein, perhaps the most interesting interactions can be found in the transmembrane domain. Unlike other BCRs, the IgM BCR has a specific heavy chain interaction with the α-β subunit of the protein. The role of BCRs is to bind to foreign antigens and initiate the appropriate immune response.

Structure

spinqualitylabelsall models Human IgM B-Cell Receptor, 7XQ8 (edited) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Antigen Binding Site Figure 1. Overview of the human B Cell Receptor and its structural components. Used with permission under Wikimedia Commons. The binding of an antigen to the human B Cell receptor is identical to other common soluble antibodies (such as IgG, IgA, IgM, IgE, or IgD). The antibody portion of the B Cell Receptor is roughly "Y" shaped and consists of two identical heavy and two identical light chains creating two similar epitope or binding regions. Thus, two antigen molecules can bind independent of one another to produce a response. Within this structure, there are both constant and variable regions. The stem of the "Y" is a constant region (Fc) composed of only heavy chain interactions. The two heavy chains then branch at a flexible hinge region. These interact individually with one light chain creating two Fab fragments or branches of the "Y". Each Fab fragment additionally contains a variable region (Fv) and a constant region. The variable region sits on top of the constant region and consists of hyper-variable loops which are random coils of amino acids that are unique to an antibody and exposed to allow specific recognition of an antigen. Furthermore, the light chains interact with the heavy chains via weak intermolecular forces and disulfide bridges. Therefore, binding to an antigen is processed through intermolecular interactions and is specific due to unique hyper variable loop sequences. Fc and α/β Interactions While the antigen binding site structure of the mIgM BCR is identical to other common soluble antibodies, there are several intracellular interactions between the heavy chains and Igα/β subunits that make it unique. In the Fc portion of the structure, the two heavy chains interact via a disulfide bond and form an O-shaped ring. Additionally, the Fc portion binds the Ig α/β heterodimer with 1:1 stoichiometry. . Due to the orientation of the heavy chains in the O-shaped ring, only Heavy chain 1 (Hc1) forms direct interactions with the Igα/β heterodimer. Furthermore, Hc1 and Igα interact through two hydrogen bonds (T75-Q487 and N73-Q493) which are stabilized by sandwiching of aromatic residues (W76 sandwiched between F358 and F485). Similarly, Hc1 and Igβ interact through three hydrogen bonds (Y66-R491, K62-T530, and R55-T533,). The residues involved in the interactions at the heavy chain and Igα/β interface are highly conserved across all species, suggesting a conserved mode of interaction. . The Igα/β heterodimer is an obligate component of all BCRs. Igα and Igβ non-covalently associate with mIgM, and are crucial components for initiating biochemical signaling inside the B cell upon antigen binding. . Igα and Igβ are associated by a disulfide bond between cystine residues (C119-C136). The disulfide bond is stabilized by π-π stacking (Y122 and F52) and a hydrogen bond (G120-R51). These residues are highly conserved across species, suggesting conservation of the Igα/β interface. Transmembrane Interactions Many transmembrane interactions can be found within a IgM B-cell receptor. The α and β subunits have numerous interactions that keep them associated with each other. An overview of all residue interactions can be found here (highlighted in green). At a cellular pH, various amino acid residues found in the transmembrane region are charged as well, which strengthens the overall interaction. For example, a hydrogen bond between residues N155 and E138, along with numerous other hydrogen bonds, works to stabilize the α-β chain interactions. Further down the chains, interactions between residues T166 and E148 also have strong hydrogen bonding. Overall, these hydrogen bonds and ion interactions work to maintain the association of the α-β chains.

Function

Once bound to an antigen, BCRs undergo a conformational change in the extracellular region. While the exact conformational change is still not known, preliminary studies suggest that there is separation of Fab fragments that opens the binding site within the BCR(ref). This initiates several signal transduction pathways, which are responsible for processing the antigen and initiating the appropriate immune responses. More specifically, the α-β subunit is connected to the phosphorylation of an immunoreceptor tyrosine-based activation motif(ITAM) upon binding. This in turn triggers the activation of kinases downstream that aid in the immune response. BCRs can be oligomeric prior to antigen binding, but once bound become an active monomer. .

Medical Relevancy

B-cell Formation

Figure 2. The Signal pathway for the response to an antigen by the B-cell receptor. Image obtained from Sino Biological.

The formation of B-cells occurs in the bone marrow from hematopoietic stem cells. Once formed, B-cell receptors are attached to B-cells through the aid of membrane-bound proteins in bone marrow cells. During this process, gene recombination occurs, which allows unique BCRs to become highly specific to different antigens.

Disease

B-cells and their respective receptors play an important role in the immune response. Therefore, if the receptors were to not function properly, there would be damaging consequences. Autoimmune disease is suggested to occur when somatic cells are recognized as foreign antigens and the body tries to eliminate them. Although the exact mechanism of disease has not been provided, it is thought that B-cell receptors are an essential part of these diseases due to their function and role in the immune systems. B-cell receptors are improperly recognizing somatic cells from different tissues depending on the disease and elicit the production of antibodies against them (autoantibodies). This causes destruction of these cell types. Examples of these diseases include rheumatoid arthritis where the lining of joints is targeted and degraded, multiple sclerosis which targets the myelin sheath that surrounds nerve cells, type 1 diabetes mellitus where the insulin producing cells are targeted for destruction, and systematic lupus erythematosus where multiple organ systems are targeted (skin, brain, lungs, and kidneys are common targets). Research on B-cells therefore has high importance in medicine and its advancement.