A key amino acid determining G3m(b) allotypic markers

Area of Science:

• Immunogenetics
• Protein Chemistry
• Structural Biology

Background:

• The Gm system is a set of human allotypic markers on immunoglobulin G (IgG) antibodies, crucial for immune response and diagnostics.
• Specific Gm markers, such as the b allotypes (b0, b3, b5), are defined by variations in IgG proteins, but the precise molecular basis has been under investigation.

Purpose of the Study:

• To identify the specific amino acid substitutions responsible for the allotypic Gm b specificities.
• To elucidate the structural changes in IgG Fc fragments that underlie these Gm b markers.

Main Methods:

• Sequence analysis of pFc' fragments from human myeloma proteins of IgG1 and IgG3 subclasses.
• Integration of crystallographic data of IgG-Fc to understand residue proximity and structural implications.

Main Results:

• A key amino acid substitution, serine at position 384, was identified as responsible for the specificities of Gm b0, b3, and b5 markers.
• In IgG3, the combination of serine at position 384 and isoleucine at position 422 was found to induce structural changes linked to Gm b markers.
• These critical residues are located in close proximity within the CH3 domain of the IgG Fc fragment.

Conclusions:

• The study pinpoints specific amino acid residues, serine at 384 and isoleucine at 422 (in IgG3), as the primary determinants of Gm b allotypic specificities.
• Structural analysis suggests these residues contribute to conformational changes in the CH3 domain, influencing antibody allotype expression.