Human IgG4: a structural perspective.
IgG4, the least represented human IgG subclass in serum, is an intriguing antibody with unique biological properties, such as the ability to undergo Fab-arm exchange and limit immune complex formation. The lack of effector functions, such as antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity, is desirable for therapeutic purposes. IgG4 plays a protective role in allergy by acting as a blocking antibody, and inhibiting mast cell degranulation, but a deleterious role in malignant melanoma, by impeding IgG1-mediated anti-tumor immunity. These findings highlight the importance of understanding the interaction between IgG4 and Fcγ receptors. Despite a wealth of structural information for the IgG1 subclass, including complexes with Fcγ receptors, and structures for intact antibodies, high-resolution crystal structures were not reported for IgG4-Fc until recently. Here, we highlight some of the biological properties of human IgG4, and review the recent crystal structures of IgG4-Fc. We discuss the unexpected conformations adopted by functionally important Cγ2 domain loops, and speculate about potential implications for the interaction between IgG4 and FcγRs.
Randall Division of Cell and Molecular Biophysics, King's College London, London, UK.|Medical Research Council & Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK.
Anna M
AM
Davies
Randall Division of Cell and Molecular Biophysics, King's College London, London, UK.|Medical Research Council & Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK.
Brian J
BJ
Sutton
D000818:Animals; D000915:Antibody Affinity / Q000276:immunology; D000918:Antibody Specificity / Q000276:immunology; D001665:Binding Sites; D015922:Complement C1q / Q000276:immunology / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology / Q000628:therapy; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000378:metabolism; D007074:Immunoglobulin G / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism / Q000627:therapeutic use; D008958:Models, Molecular; D009369:Neoplasms / Q000276:immunology / Q000628:therapy; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D017452:Receptors, IgG / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D017452:Receptors, IgG; D015922:Complement C1q
Fc receptor; IgG1; IgG4; antibody; immunoglobulin