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H. sapiens mIgM B Cell Receptor

spinqualitylabelsall models Human mIgM B Cell Receptor. Heavy chain 1 is represented in blue, heavy chain 2 in magenta, light chain 1 in green, and light chain 2 in yellow. Iga is shown in red while Igb is in orange. 7XQ8 Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image Contents 1 Introduction 2 Structure 3 Antigen Binding Site 4 Heavy Chain Interactions (Iga and IgB) 5 Transmembrane Interactions 6 Function 7 Proposed Conformational Changes 8 Signal Pathway Introduction Structure Figure 2. Diagram of the human B Cell Receptor with the Fab fragments, binding region, variable regions, constant regions and Iga/ Igb labelled. Heavy chain 1 is represented in blue, heavy chain 2 in magenta, light chain 1 in green, and light chain 2 in yellow. Disulfide bridges are represented with solid black lines connecting the heavy chains to themselves and to the light chains. Figure 2. The Signal pathway for the response to an antigen by the B-cell receptor. Illustration reproduced courtesy of Cell Signaling Technology, Inc. (www.cellsignal.com). 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 and two identical chains creating two similar epitope binding regions[1] (figure 1). Two antigen molecules can bind independent of one another to produce a response. Matching with standard FABs, the Ig portion has constant and variable region. The stem of the "Y" is a (, Fc) composed of only heavy chain interactions[1]. The two heavy chains then branch at a flexible (). These interact individually with one light chain creating two Fab fragments or branches of the "Y"[1]. Light and heavy chains are held together via weak intermolecular forces and disulfide bridges[1]. Each () then terminates with two (), (Fv). These variable regions consist of hyper-variable loops, desired random coils of amino acids selected for specific recognition of a desired antigen [1]. Binding to an antigen is determined based on intermolecular interactions to the hyper variable loops, and selectivity is provided by unique hyper variable loop sequences. Due to the identical structure of Fab fragments, BCR will recognize antigens in the same manner as do free antibodies. This is emphasized through Ma et al. who studied the IgG- BCR (VRC01) that targets gp120 of HIV-1 showing that the BCR form has an identical structure to the free antibody version (citation). This leads to a conformational change in the protein and transmits the signal through the membrane (citation). Heavy Chain Interactions (Iga and IgB) Transmembrane Interactions Function Proposed Conformational Changes Signal Pathway

Medical Relevancy

Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001.

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).

Therapeutics

Additionally, B-cells have been studied in use for other therapies. For instance, research on mice has shown that manipulation of the genetic composition of their epitope region to recognize an antigen specific to cancer cells, reduced overall tumor size ^[2]. Furthermore, the B-cell signal pathway has been researched as a target in therapies for Chronic Lymphocytic Leukemia (CLL). This disease arises from the overproduction of B-cell and other immune cells that are nonfunctional. Research regarding this pathway has focused on producing antagonists for certain kinases that cause this over proliferation of cells and has had initial success ^[3]. The engineering of B-cells and manipulation of its biochemical pathway has promising uses in medicine.

B Cell formation/ function

Structure Summary The BCR is anchored to the membrane through the transmembrane regions and its interactions. Upon antigen binding, the BCR will undergo a unique structural conformation change that will allow transmission of the signal through the extracellular regions and the cell membrane to elicit an intracellular response. Interaction with a foreign antigen occurs at hyper-variable loop regions and causes the separation of Fab fragments (citation). This structural, conformational change will be transmitted through the heavy chains to the interface of heavy chain 1 and the Iga/ Igb complex. A shifting of interactions and overall conformational changes due to binding will then carry the signal through the Iga/ Igb complex through the membrane and into the cell. This will trigger intracellular signaling that will elicit subsequent production of free antibodies to recognize and target the foreign antigen. Therefore, any improper functioning of one of these regions will lead to improper functioning of the BCR and lessen the immune response as a whole.

3D structures of the BCR

3D structures of the BCR

References

1. ↑ ^{1.0 1.1 1.2 1.3 1.4} Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001.
2. ↑ Page A, Hubert J, Fusil F, Cosset FL. Exploiting B Cell Transfer for Cancer Therapy: Engineered B Cells to Eradicate Tumors. Int J Mol Sci. 2021 Sep 16;22(18):9991. doi: 10.3390/ijms22189991. PMID: 34576154; PMCID: PMC8468294.
3. ↑ Woyach JA, Johnson AJ, Byrd JC. The B-cell receptor signaling pathway as a therapeutic target in CLL. Blood. 2012 Aug 9;120(6):1175-84. doi: 10.1182/blood-2012-02-362624. Epub 2012 Jun 19. PMID: 22715122; PMCID: PMC3418714.