Human FcRL5 is an Fc receptor that simultaneously engages two IgGs

Area of Science:

• Immunology
• Structural Biology
• Molecular Biology

Background:

• Fc receptors are critical for immunoglobulin effector functions.
• Fc receptor-like 5 (FcRL5) is a target in B cell malignancies and suspected to bind IgG.
• The precise molecular mechanism of FcRL5-IgG interaction was previously unknown.

Purpose of the Study:

• To elucidate the molecular mechanism by which FcRL5 binds immunoglobulin G (IgG).
• To characterize the structural basis of FcRL5-Fcγ interaction and its functional implications.
• To investigate the role of FcRL5 in recognizing and internalizing IgG immune complexes.

Main Methods:

• Utilized cryo-electron microscopy to determine the structure of FcRL5 bound to Fcγ.
• Performed binding assays to assess FcRL5 interaction with Fcγ molecules and IgG immune complexes (ICs).
• Investigated the internalization capacity of FcRL5 for IgG polymers and ICs.

Main Results:

• Human FcRL5 functions as a bona fide IgG-Fc (Fcγ) receptor, distinct from its mouse counterpart.
• FcRL5 requires two closely positioned Fcγ molecules for robust binding, optimally engaging them at a 60° angle.
• Structural analysis revealed a unique binding mode involving FcRL5 D1-D2 and D3 domains interacting with two Fcγ molecules.
• FcRL5 specifically recognizes IgG immune complexes, with binding affinity correlating to IgG concentration.
• FcRL5 demonstrated the ability to internalize IgG polymers and immune complexes.

Conclusions:

• FcRL5 employs a unique avidity-driven binding mechanism to recognize IgG immune complexes.
• The findings provide structural insights into a novel Fcγ-FcγR binding mode.
• This study clarifies FcRL5 function, highlighting its role in IgG recognition and internalization, relevant to B cell malignancies.