Anti-HIV-1 B cell antigen receptor signaling and structure

Area of Science:

• Immunology
• Structural Biology
• Molecular Biology

Background:

• The B cell antigen receptor (BCR) complex initiates B cell activation through antigen recognition and signaling.
• Existing structural data on BCRs lacks detail on antigen-binding domain (Fab) disposition and antigen-induced signaling mechanisms.

Purpose of the Study:

• To investigate antigen affinity and signaling of immunoglobulin (Ig) M and G BCRs.
• To define conformational states of full-length BCRs from specific human broadly neutralizing antibodies.
• To elucidate the structural basis of antigen-induced BCR signal transmission.

Main Methods:

• Utilized cryo-electron microscopy (cryo-EM) to determine structures of full-length BCR complexes.
• Assessed antigen affinity and signaling capabilities of different BCR isotypes (IgM and IgG).
• Analyzed conformational states and Fab orientations of BCRs bound to specific antigens.

Main Results:

• BCRs adopted distinct I-shaped (2G12) and Y-shaped (CH31) conformations mirroring their soluble antibody forms.
• Both IgM and IgG BCRs of the same specificity exhibited similar affinities for target antigens (Env trimers).
• Antigen valency-dependent differential signaling was observed for 2G12 IgM and IgG BCRs; cryo-EM revealed varied Fab orientations, highlighting BCR flexibility.

Conclusions:

• The study presents a novel dynamic model of the B cell antigen receptor complex.
• Structural insights reveal flexibility and hinge regions crucial for BCR dynamics.
• Findings provide a foundation for understanding how antigen binding triggers BCR signaling.