On Aug. 19, Prof. Yigong Shi and his team at Westlake University published a paper entitled "Cryo-EM Structure of the Human IgM B Cell Receptor" in Science, reporting a 3.3 Å cryo-electron microscope (cryo-EM) structure of human IgM B cell receptor (IgM-BCR) for the first time. The high-resolution structure, revealing the molecular mechanism of IgM-BCR assembly, provides a key structural basis for immunotherapy.

Screenshot of the paper

Paper link: http://doi.org/10.1126/science.abo3923

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B cells are a critical component of the adaptive immune system. B cell activation is triggered by antigen binding to the B cell receptor (BCR). Then B cells proliferate and differentiate to form either plasma cells that secrete protective antibodies against potential pathogens, or memory cells that provide long-lived protection against secondary infection.

The BCR is a multi-subunit complex composed of a membrane-bound immunoglobulin (mIg) and a heterodimer of the Igα and Igβ subunits. The mIg can be one of five different immunoglobulin isotypes, including IgM, IgD, IgG, IgA, and IgE. It is also responsible for antigen binding, but it lacks the signaling motif, necessitating Igα/Igβ to transduce the signals. Upon antigen binding, BCR is clustered on the plasma membrane, initiating a signaling cascade.

The BCR signaling pathway has also been identified as an important therapeutic target for B cell malignancies, as activation of BCR signaling promotes the survival and growth of malignant B cells in patients with these tumors.

The components of BCR were identified in 1990 by Michael Reth's group at the Max Planck Institute in Germany. In the following decades, intensive studies were focused on how the extracellular domain recognizes various antigens and activates B cell signaling pathways, but the fundamental question of how BCR is assembled has remained unanswered. In addition, high-resolution structures are required to understand B cell activation and to facilitate therapeutic development targeting this complex.

To address these important questions, Dr. Qiang Su, a postdoctoral fellow in the Shi lab, worked together with the team to generate an IgM-BCR complex by co-expressing the components of human IgM-BCR together with an endoplasmic reticulum retention protein pERp1, which was reported to facilitate the folding of IgM-BCR, in mammalian cells. They then purified the complex and resolved its structure to an overall resolution of 3.3 Å using single-particle cryo-EM (Figure. 1)

Figure 1 Overall structure of the IgM-BCR complex

IgM-BCR consists of two mIgM heavy chains, two light chains, and two membrane-anchored signaling subunits, Igα and Igβ. The ectodomain of the heavy chain tightly packs against the ectodomain of the Igα/Igβ heterodimer. In the juxtamembrane region, one of the two heavy chains traverses through a ring structure surrounded by an Igα/Igβ heterodimer. The transmembrane helices (TM) of mIgM and Igα/Igβ form a four-helix bundle stabilized by hydrogen bonds among the transmembrane helices (Figure 2). In addition, the structure reveals 14 glycosylation sites on the ectodomain and three potential antibody recognition sites that may contribute to the rational design of therapeutic antibodies and mini-proteins for disease intervention (Figure 3).

Figure 2 Interchain interaction of IgM-BCR complex assembly

Figure 3 Distribution of IgM-BCR glycosylation sites

Shi and Su from the School of Life Sciences of Westlake University are the co-corresponding authors. The EM data were collected at the cryo-EM facility of Westlake University, and the computation was supported by the High-performance Computing Center of Westlake University. This work was supported by the National Natural Science Foundation of China, the Key R&D Program of Zhejiang Province, and the National Key R&D Program of China.