Disulfide connectivity of human immunoglobulin G2 structural isoforms.
In this communication we present the detailed disulfide structure of IgG2 molecules. The consensus structural model of human IgGs represents the hinge region positioned as a flexible linker connecting structurally isolated Fc and Fab domains. IgG2 molecules are organized differently from that model and exhibit multiple structural isoforms composed of (heavy chain-light chain-hinge) covalent complexes. We describe the precise connection of all the disulfide bridges and show that the IgG2 C H1 and C-terminal C L cysteine residues are either linked to each other or to the two upper hinge cysteine residues specific to the IgG2 subclass. A defined arrangement of these disulfide bridges is unique to each isoform. Mutation of a single cysteine residue in the hinge region eliminates these natural complexes. These results show that IgG2 structure is significantly different from the conventionally accepted immunoglobulin structural model and may help to explain some of the unique biological activity attributed only to this subclass.
Department of Analytical and Formulation Sciences, Process and Product Development, Amgen, Inc., Seattle, Washington 98119, USA.
Theresa
T
Martinez
Amy
A
Guo
Martin J
MJ
Allen
Mei
M
Han
Danielle
D
Pace
Jay
J
Jones
Ron
R
Gillespie
Randal R
RR
Ketchem
Yuling
Y
Zhang
Alain
A
Balland
D004220:Disulfides; D019075:Electrophoresis, Capillary; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry; D007074:Immunoglobulin G / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification; D008958:Models, Molecular; D010449:Peptide Mapping; D011487:Protein Conformation; D020033:Protein Isoforms
D004220:Disulfides; D007140:Immunoglobulin Fab Fragments; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D020033:Protein Isoforms