Sandbox Reserved 1772: Difference between revisions

While the antigen binding site structure of the mIgM BCR is identical to common soluble antibodies, intermolecular interactions between the heavy chains and Igα/β subunits provide the emergent receptor properties. In the Fc portion of the structure, the two heavy chains interact via a disulfide bond and form an <scene name='95/952700/O-shaped_ring/17'>O-shaped ring</scene>. Additionally, the Fc portion binds the <scene name='95/952700/O-shaped_ring/13'>Ig α/β heterodimer</scene> <scene name='95/952700/O-shaped_ring/15'>(heterodimer zoomed)</scene> with 1:1 stoichiometry. <Ref name="Tolar P"> 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. PMID: 35981020.] </Ref>. 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. To correspond with the 3D representations, Hc1 residues will be represented in blue, Igα residues will be represented in red, and Igβ residues will be represented in orange. Furthermore, <scene name='95/952700/Ig-a_and_hc_1/6'>Hc1 and Igα interact</scene> through two hydrogen bonds (<b><span class="text-red">T75</span></b>-<b><span class="text-blue">Q487</span></b> and <b><span class="text-red">N73</span></b>-<b><span class="text-blue">Q493</span></b>) which are stabilized by sandwiching of aromatic residues (<b><span class="text-red">W76</span></b> sandwiched between <b><span class="text-blue">F358</span></b> and <b><span class="text-blue">F485</span></b>). Similarly, <scene name='95/952700/Igb_and_hc/6'>Hc1 and Igβ interact</scene> through three hydrogen bonds (<b><span class="text-orange">Y66</span></b>-<b><span class="text-blue">R491</span></b>, <b><span class="text-orange">K62</span></b>-<b><span class="text-blue">T530</span></b>, and <b><span class="text-orange">R55</span></b>-<b><span class="text-blue">T533</span></b>). 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. <Ref name="Su Q"> Su Q, Chen M, Shi Y, Zhang X, Huang G, Huang B, Liu D, Liu Z, Shi Y. Cryo-EM structure of the human IgM B cell receptor. Science. 2022 Aug 19;377(6608):875-880. [doi: 10.1126/science.abo3923. Epub 2022 Aug 18. PMID: 35981043.]</Ref>. The Igα/β heterodimer is composed of a transmembrane domain, which consists of two hydrophobic helices, and an extracellular domain, which forms an interface with and Hc1. 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. <Ref name="Tolar P"> 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. PMID: 35981020.] </Ref>. <scene name='95/952700/Iga_and_igb/1'>Igα and Igβ are connected</scene> by a disulfide bond between cystine residues (<b><span class="text-red">C119</span></b>-<b><span class="text-orange">C136</span></b>). The disulfide bond is further stabilized by π-π stacking (<b><span class="text-red">Y122</span></b> and <b><span class="text-orange">F52</span></b>) and a hydrogen bond (<b><span class="text-red">G120</span></b>-<b><span class="text-orange">R51</span></b>). These residues in Igα/β are highly conserved across species, suggesting conservation of the Igα/β interface. <Ref name="Su Q"> Su Q, Chen M, Shi Y, Zhang X, Huang G, Huang B, Liu D, Liu Z, Shi Y. Cryo-EM structure of the human IgM B cell receptor. Science. 2022 Aug 19;377(6608):875-880. [doi: 10.1126/science.abo3923. Epub 2022 Aug 18. PMID: 35981043.]</Ref>.