Sandbox Reserved 1786: Difference between revisions

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[[Image:IgM_structure_overview_diagram.png|500 px|right|thumb|'''Figure 1. IgM BCR Structure Overview.''' Depiction of the IgM BCR expressed on the membrane of a B cell. Includes all major components including the α/β heterodimer, heavy and light chains, antigen binding sites, and the ITAM region for signal transduction.]]

<div style="text-align: justify">The IgM BCR consists of six separate chains (Figure 1) that make up the three main [https://en.wikipedia.org/wiki/Protein_domain domains] typically found in a [https://bioxcell.com/educational-articles/antibody-structure/ general antibody structure]. A depiction of the IgM <scene name='95/952714/Colored_by_domain/6'>colored by domain</scene> shows two heavy and two light chains that together form the Fab region, or variable fragment at the top of the molecule where the antigen binding sites are located. The two heavy chains extend below the Fab region through the Fc region and eventually connect to the Igα/β heterodimer to form the transmembrane region which anchors the overall complex to the B cell. These regions are also labeled in Figure 1. The overall structure, expression, and function of the IgM BCR is strongly influenced by the transmembrane region in which Ig α/β interactions as a heterodimer influence cell surface expression, receptor assembly, and effective signal transduction. <ref name="Tolar">Tolar P, Pierce SK. Unveiling the B cell receptor structure. Science. 2022 Aug 19;377(6608):819-820. doi: 10.1126/science.add8065. Epub 2022 Aug 18.[http://dx.doi.org/10.1126/science.add8065 DOI:10.1126/science.add8065</ref>, <ref name="Dylke">Dylke J, Lopes J, Dang-Lawson M, Machtaler S, Matsuuchi L. Role of the extracellular and transmembrane domain of Ig-alpha/beta in assembly of the B cell antigen receptor (BCR). Immunol Lett. 2007 Sep 15;112(1):47-57. doi: 10.1016/j.imlet.2007.06.005. Epub 2007 Jul 23. [http://dx.doi.org/10.1016/j.imlet.2007.06.005 DOI:10.1016/j.imlet.2007.06.005</ref>. In each domain, interactions between individual chains are important to understand the complex as a whole. All future 3D depictions showing these interactions ues the same PyMOL file [https://www.rcsb.org/structure/7XQ8 (7xq8)] and will be <scene name='95/952714/Colored_by_chain/12'>colored by chain</scene> as in Figure 1.

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===Transmembrane Region===

~~<div style="text-align: left>~~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 Igα and Igβ 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] (NAGs) in the extracellular region of both the Igα and and Igβ 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 Igα and Igβ subunits until dimerization occurs. <ref name="Dylke"/>

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 Igα and Igβ 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] (NAGs) in the extracellular region of both the Igα and and Igβ 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 Igα and Igβ subunits until dimerization occurs. <ref name="Dylke"/>

After Igα and Igβ dimerization, the transmembrane helices of the heavy chains can embed within the B-cell membrane and intertwine with the Igα and Igβ 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 alpha, beta, and heavy chains ('''{{Font color|violet|A}}'''/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 Igα and Igβ chains. <ref name="Dylke"/>

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@@ Line 12: / Line 12: @@
 [[Image:IgM_structure_overview_diagram.png|500 px|right|thumb|'''Figure 1. IgM BCR Structure Overview.''' Depiction of the IgM BCR expressed on the membrane of a B cell. Includes all major components including the α/β heterodimer, heavy and light chains, antigen binding sites, and the ITAM region for signal transduction.]]
 <div style="text-align: justify">The IgM BCR consists of six separate chains (Figure 1) that make up the three main [https://en.wikipedia.org/wiki/Protein_domain domains] typically found in a [https://bioxcell.com/educational-articles/antibody-structure/ general antibody structure]. A depiction of the IgM <scene name='95/952714/Colored_by_domain/6'>colored by domain</scene> shows two heavy and two light chains that together form the <b><span class="text-cyan">Fab region</span></b>, or variable fragment at the top of the molecule where the antigen binding sites are located. The two heavy chains extend below the <b><span class="text-cyan">Fab region</span></b> through the <b><span class="text-purple">Fc region</span></b> and eventually connect to the Igα/β heterodimer to form the <b><span class="text-orange">transmembrane region</span></b> which anchors the overall complex to the B cell. These regions are also labeled in Figure 1. The overall structure, expression, and function of the IgM BCR is strongly influenced by the <b><span class="text-orange">transmembrane region</span></b> in which Ig α/β interactions as a heterodimer influence cell surface expression, receptor assembly, and effective signal transduction. <ref name="Tolar">Tolar P, Pierce SK. Unveiling the B cell receptor structure. Science. 2022 Aug 19;377(6608):819-820. doi: 10.1126/science.add8065. Epub 2022 Aug 18.[http://dx.doi.org/10.1126/science.add8065 DOI:10.1126/science.add8065</ref>, <ref name="Dylke">Dylke J, Lopes J, Dang-Lawson M, Machtaler S, Matsuuchi L. Role of the extracellular and transmembrane domain of Ig-alpha/beta in assembly of the B cell antigen receptor (BCR). Immunol Lett. 2007 Sep 15;112(1):47-57. doi: 10.1016/j.imlet.2007.06.005. Epub 2007 Jul 23. [http://dx.doi.org/10.1016/j.imlet.2007.06.005 DOI:10.1016/j.imlet.2007.06.005</ref>. In each domain, interactions between individual chains are important to understand the complex as a whole. All future 3D depictions showing these interactions ues the same PyMOL file [https://www.rcsb.org/structure/7XQ8 (7xq8)] and will be <scene name='95/952714/Colored_by_chain/12'>colored by chain</scene> as in Figure 1.
@@ Line 18: / Line 19: @@
 ===Transmembrane Region===
-<div style="text-align: left>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"/>
+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"/>
 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"/>