3sgk
From Proteopedia
Unique carbohydrate/carbohydrate interactions are required for high affinity binding of FcgIII and antibodies lacking core fucose
Structural highlights
Disease[IGHG1_HUMAN] Defects in IGHG1 are a cause of multiple myeloma (MM) [MIM:254500]. MM is a malignant tumor of plasma cells usually arising in the bone marrow and characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria and anemia. Complications of multiple myeloma are bone pain, hypercalcemia, renal failure and spinal cord compression. The aberrant antibodies that are produced lead to impaired humoral immunity and patients have a high prevalence of infection. Amyloidosis may develop in some patients. Multiple myeloma is part of a spectrum of diseases ranging from monoclonal gammopathy of unknown significance (MGUS) to plasma cell leukemia. Note=A chromosomal aberration involving IGHG1 is found in multiple myeloma. Translocation t(11;14)(q13;q32) with the IgH locus. Translocation t(11;14)(q13;q32) with CCND1; translocation t(4;14)(p16.3;q32.3) with FGFR3; translocation t(6;14)(p25;q32) with IRF4. [FCG3A_HUMAN] The disease is caused by mutations affecting the gene represented in this entry.[1] [2] [3] [4] Function[FCG3A_HUMAN] Receptor for the Fc region of IgG. Binds complexed or aggregated IgG and also monomeric IgG. Mediates antibody-dependent cellular cytotoxicity (ADCC) and other antibody-dependent responses, such as phagocytosis.[5] [6] Publication Abstract from PubMedAntibody-mediated cellular cytotoxicity (ADCC), a key immune effector mechanism, relies on the binding of antigen-antibody complexes to Fcgamma receptors expressed on immune cells. Antibodies lacking core fucosylation show a large increase in affinity for FcgammaRIIIa leading to an improved receptor-mediated effector function. Although afucosylated IgGs exist naturally, a next generation of recombinant therapeutic, glycoenginereed antibodies is currently being developed to exploit this finding. In this study, the crystal structures of a glycosylated Fcgamma receptor complexed with either afucosylated or fucosylated Fc were determined allowing a detailed, molecular understanding of the regulatory role of Fc-oligosaccharide core fucosylation in improving ADCC. The structures reveal a unique type of interface consisting of carbohydrate-carbohydrate interactions between glycans of the receptor and the afucosylated Fc. In contrast, in the complex structure with fucosylated Fc, these contacts are weakened or nonexistent, explaining the decreased affinity for the receptor. These findings allow us to understand the higher efficacy of therapeutic antibodies lacking the core fucose and also suggest a unique mechanism by which the immune system can regulate antibody-mediated effector functions. Unique carbohydrate-carbohydrate interactions are required for high affinity binding between Fc{gamma}RIII and antibodies lacking core fucose.,Ferrara C, Grau S, Jager C, Sondermann P, Brunker P, Waldhauer I, Hennig M, Ruf A, Rufer AC, Stihle M, Umana P, Benz J Proc Natl Acad Sci U S A. 2011 Jul 18. PMID:21768335[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Human | Large Structures | Benz, J | Bruenker, P | Ferrara, C | Grau, S | Hennig, M | Jaeger, C | Ruf, A | Rufer, A C | Sondermann, P | Stihle, M | Umana, P | Waldhauer, I | Afucosylation | Antibody | Fc receptor | Immune system
