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H. sapiens mIgM B Cell Receptor

1 Introduction
2 Structure
3 Function
- 3.1 Proposed Conformational Changes
- 3.2 Signal Pathway

Introduction

Structure

The BCR consists of a membrane-bound immunoglobulin (mIg) and two signal-transducing subunits, Igα and Igβ. The mIg consists of two heavy chains and two light chains. Antigen binding at the binding site triggers signal transduction by Igα and Igβ. Both consist of an extracellular, Ig-like domain, and an intracellular immunoreceptor tyrosine-based activation motif. ^[1].

Antigen Binding Site

Heavy Chain Interactions (Igα and Igβ)

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 . Additionally, the Fc portion binds the with 1:1 stoichiometry. ^[2]. 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, through two hydrogen bonds (T75-Q487 and N73-Q493) which are stabilized by sandwiching of aromatic residues (W76 sandwiched between F358 and F485). Similarly, 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. ^[1]. 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. ^[2]. 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

Function

Proposed Conformational Changes

^[3].

Signal Pathway

Medical Relevancy

References

↑ ^1.0 ^1.1 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.]
↑ ^2.0 ^2.1 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.]
↑ ShenSichen Z, LiZhengpeng L, Liu W,(2019) Conformational change within the extracellular domain of B cell receptor in B cell activation upon antigen binding [eLife 8:e42271. https://doi.org/10.7554/eLife.42271]

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 ===Heavy Chain Interactions (Igα and Igβ)===
-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/1'>O-shaped ring</scene>. Additionally, the Fc portion binds the <scene name='95/952700/O-shaped_ring/7'>Ig α/β heterodimer</scene> <scene name='95/952700/O-shaped_ring/2'>(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. Furthermore, <scene name='95/952700/Ig-a_and_hc_1/3'>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 (W76 sandwiched between F358 and F485). Similarly, <scene name='95/952700/Igb_and_hc/1'>Hc1 and Igβ interact</scene> 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. <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 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 associated</scene> 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.
+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/1'>O-shaped ring</scene>. Additionally, the Fc portion binds the <scene name='95/952700/O-shaped_ring/7'>Ig α/β heterodimer</scene> <scene name='95/952700/O-shaped_ring/2'>(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. Furthermore, <scene name='95/952700/Ig-a_and_hc_1/3'>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/1'>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 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 associated</scene> 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.
 <scene name='95/952700/Johnson_test/1'>TextToBeDisplayed</scene>