Sandbox Reserved 1786: Difference between revisions

<div style="text-align: justify">The IgM BCR is anchored to [https://en.wikipedia.org/wiki/B_cell B-cell] membranes through the <scene name='95/952714/Integral_region/15'>transmembrane region</scene> which is broken up into both extracellular and integral domains which sit on top of or span through the membrane, respectively (Figure 1). The extracellualr region is primarily composed of [https://proteopedia.org/wiki/index.php/Beta_sheet β-sheets]while the integral region is composed of [https://proteopedia.org/wiki/index.php/Alpha_helix#:~:text=An%20alpha%20helix%20is%20a,can%20be%20of%20arbitrary%20length. α-helices]. IgM BCR assembly requires dimerization of the <b><span class="text-brown">Igα</span></b> and <b><span class="text-orange">Igβ</span></b> subunits which embed within the B-cell membrane. <ref name="Tolar"/> The <scene name='95/952714/Ig_alpha_beta/5'>Igα and Igβ heterodimer</scene> dimerizes within the extracellular region with a <scene name='95/952714/Extracellular_disulfide_bridge/6'>disulfide bridge</scene>. Additional dimerization occurs within the integral region via a hydrogen bond; the residues involved have not been confirmed. Although the mechanism of disulfide bridge formation is still unknown, <scene name='95/952714/Extracellular_glycosylation/2'>glycosylation</scene> via [https://en.wikipedia.org/wiki/N-linked_glycosylation N-linked asparagine glycosyl groups] <b><span class="text-lightgreen">(NAGs)</span></b> in the extracellular region of both the <b><span class="text-brown">Igα</span></b> and and <b><span class="text-orange">Igβ</span></b> chains is hypothesized to facilitate this process. The NAG groups are believed to be essential for the recruitment of [https://en.wikipedia.org/wiki/Chaperone_(protein) Chaperone proteins] to optimize the folding process. <ref name="Daniels">PMID:12535523</ref> Past studies with human and viral proteins have shown that the presence of NAGs not only facilitate the rapid formation of disulfide bridges, but also ensure correct location. <ref name="Bakshi">PMID:35409101</ref>, <ref name="Mirazimi">PMID:9557673</ref> The recruited chaperone proteins will remain bound to the <b><span class="text-brown">Igα</span></b> and <b><span class="text-orange">Igβ</span></b> subunits until dimerization occurs. <ref name="Dylke"/>

<div style="text-align: justify">After <b><span class="text-brown">Igα</span></b> and <b><span class="text-orange">Igβ</span></b> dimerization, the transmembrane helices of the heavy chains can embed within the B-cell membrane and intertwine with the <b><span class="text-brown">Igα</span></b> and <b><span class="text-orange">Igβ</span></b> chains. <ref name="Tolar"/> The side chains of this <scene name='95/952714/Integral_helices_2/2'>4-pass integral helix structure</scene>, made up by the <b><span class="text-brown">alpha</span></b>, <b><span class="text-orange">beta</span></b>, and heavy chains ('''{{Font color|violet|A}}'''/<b><span class="text-blue">B</span></b>), are primarily hydrophobic; this allows for interactions with the hydrophobic tails in the [https://en.wikipedia.org/wiki/Lipid_bilayer phospholipid bilayer]. The four helices (Figure 2) are intertwined and primarily held together through interactions between the <scene name='95/952714/Integral_helices_2/3'>hydrophobic side chains</scene>; however, a a few polar residues are included which allow for additional interactions with the polar residues on the <b><span class="text-brown">Igα</span></b> and <b><span class="text-orange">Igβ</span></b> chains. <ref name="Dylke"/>  

[[Image:Integral_helix_figure.png|400 px|left|thumb|'''Figure 2. 4-pass integral helix.''' PyMOL image of the integral helices in IgM BCR (PDB:7xq8). The structure is shown rotated on the x and y axes to illustrate how the chains are intertwined. Side chains are shown as sticks. Brown=Ig alpha, orange=Ig beta, pink=heavy chain A, blue=heavy chain B.]]

{{Clear}}

<div style="text-align: justify">Within the transmembrane region, '''{{Font color|violet|heavy chain A}}''' and <b><span class="text-blue">heavy chain B</span></b> associate (Figure 1) asymmetrically to facilitate intracellular signaling cascades. The <scene name='95/952713/Trans_heavy/9'>transmembrane heavy chain interface</scene> allows them to pack together via [https://en.wikipedia.org/wiki/Van_der_Waals_force Van der Waals] contacts, but there are also prominent hydrogen bonds between each chain. More specifically, the hydroxyl group from Ser584 on '''{{Font color|violet|heavy chain A}}''' donates a hydrogen bond to Ser584 and to Ser588 on <b><span class="text-blue">heavy chain B</span></b>. This creates a  [https://en.wikipedia.org/wiki/Hydrogen_bond bifurcated hydrogen bond], essentially forming a “fork” between the two chains to help stabilize them and maintain the transmission of the signal once the cell is activated. Because transmembrane Ig molecules cannot efficiently initiate the signal cascade, they must associate with the <b><span class="text-brown">Igα</span></b> and <b><span class="text-orange">Igβ</span></b> chains within the BCR. <ref name="Su">PMID:35981043</ref>

<div style="text-align: justify">Furthermore, both the <b><span class="text-brown">Igα</span></b> and <b><span class="text-orange">Igβ</span></b> chains have cytoplasmic tails that extend into the B cell (Figure 1). Each of these tails contain an [https://en.wikipedia.org/wiki/Immunoreceptor_tyrosine-based_activation_motif ITAM region] to facilitate signal transduction (Figure 4). <ref name="Ma">PMID:35981028</ref> The structures of the ITAM regions have not yet been determined.  

<div style="text-align: justify">Because a conformational change occurs throughout the entirety of the IgM-BCR complex, the Fc region must be able to tolerate the contortion of the molecule as the antigen binds. In constant region two, which is located at the start of the Fc region, '''{{Font color|violet|heavy chain A}}''' and <b><span class="text-blue">heavy chain B</span></b> make a <scene name='95/952713/Disulfides/5'>disulfide bridge</scene> to stabilize the IgM-BCR and drive downstream signaling.  

<div style="text-align: justify">To maximize the Fc region’s signal transduction efficiency and Van der Waals contacts, constant region two of '''{{Font color|violet|heavy chain A}}''' makes an asymmetrical association with constant region three of <b><span class="text-blue">heavy chain B</span></b> to create a <scene name='95/952713/Trans_heavy/7'>heavy chain interface</scene>. More specifically, Arg243 and Arg251 residues from '''{{Font color|violet|heavy chain A}}''' donate three hydrogen bonds to Leu433, Thr431, and Asp376 residues on <b><span class="text-blue">heavy chain B</span></b>. Furthermore, Leu313 of heavy chain A accepts a hydrogen bond from Thr429 on heavy chain B. <ref name="Ma">PMID:35981028</ref>