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From Proteopedia
Crystal structure of a disease-associated anti-human GM-CSF autoantibody MB007
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. FunctionPublication Abstract from PubMedPolyclonal autoantibodies against human granulocyte macrophage- colony stimulating factor (hGM-CSF) are a hallmark of pulmonary alveolar proteinosis (PAP) affection and several other reported autoimmune diseases. MB007 is a high affinity anti-human GM-CSF autoantibody isolated from a patient suffering from PAP which shows only modest neutralization of GM-CSF bioactivity. We describe the first crystal structure of a cytokine directed human IgG1lambda autoantibody binding fragment (Fab) at 1.9 A resolution. Its CDR3-H substantially differs from all previously reported VH7 germline IgG1 structures. We derive a reliable model of the antigen:autoantibody complex by using NMR chemical shift perturbation data in combination with computational methods. Superposition of the modeled complex structure with the human GM-CSF/GM-CSF ternary receptor complex reveals only little overlap between receptor and Fab when bound to GM-CSF. Our model provides a structural basis for understanding the mode-of-action of the MB007 autoantibody. Molecular structure of human GM-CSF in complex with a disease-associated anti-human GM-CSF autoantibody and its potential biological implications.,Blech M, Seeliger D, Kistler B, Bauer MM, Hafner M, Horer S, Zeeb M, Nar H, Park JE Biochem J. 2012 Jul 27. PMID:22839360[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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