Human IgG2 antibody disulfide rearrangement in vivo.
Proteins destined to circulate in the blood are first folded and assembled in the endoplasmic reticulum of secretory cells. For antibodies, like many other serum proteins, the folding and assembly steps involve the formation of disulfide bonds. Such bonds have been thought to be static features of proteins, stabilizing domains, and linking polypeptide chains, although some cases of extracellular disulfide bond cleavage have been noted. Recently, the human IgG2 antibody subclass was found to possess multiple structures differing in specific disulfide linkages. These structures are naturally occurring and can, in some cases, affect the activity of the antibody. Here we show that these IgG2 disulfide linkages interconvert while circulating in humans. Secretory cells initially produce primarily one form (IgG2-A), which is rapidly converted to a second form (IgG2-A/B) while circulating in the blood, followed by a slower conversion to a third form (IgG2-B). This work demonstrates that the disulfide structure of the IgG2 antibody is dynamic in vivo, on a time scale similar to that of the protein's lifetime. Thus, changes to the IgG2 disulfide structure provide a marker of the protein's age and may alter its activity over its lifetime.
Liu
Y Diana
YD
Department of Analytical and Formulation Sciences, Amgen, Incorporated, Thousand Oaks, California 91320, USA.
Chen
Xiaoyu
X
Enk
Jian Zhang-van
JZ
Plant
Matt
M
Dillon
Thomas M
TM
Flynn
Gregory C
GC
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004220:Disulfides / Q000737:chemistry; D019075:Electrophoresis, Capillary; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007074:Immunoglobulin G / Q000737:chemistry*; D008024:Ligands; D010455:Peptides / Q000737:chemistry; D011134:Polysaccharides / Q000737:chemistry; D013438:Sulfhydryl Compounds / Q000737:chemistry
D000911:Antibodies, Monoclonal; D004220:Disulfides; D007074:Immunoglobulin G; D008024:Ligands; D010455:Peptides; D011134:Polysaccharides; D013438:Sulfhydryl Compounds