Antibody-mediated cellular cytotoxicity (ADCC), a key immune effector mechanism, relies on the binding of antigen-antibody complexes to Fcγ receptors expressed on immune cells. Antibodies lacking core fucosylation show a large increase in affinity for FcγRIIIa 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 Fcγ 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 carbohydratecarbohydrate 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.immunoglobulin | afucosylation | antibody effector function | X-ray crystallography
Human HtrA1 belongs to a widely conserved family of serine proteases involved in various aspects of protein quality control and cell fate. Although HtrA1 has been implicated in the pathology of several diseases, its precise biological functions remain to be established. Through identification of potential HtrA1 targets, studies presented herein propose that within the context of arthritis pathology HtrA1 contributes to cartilage degradation. Elevated synovial HtrA1 levels were detected in fluids obtained from rheumatoid and osteoarthritis patients, with synovial fibroblasts identified as a major source of secreted HtrA1. Mass spectrometry analysis of potential HtrA1 substrates within synovial fluids identified fibronectin as a candidate target, and treatment of fibronectin with recombinant HtrA1 led to the generation of fibronectin-degradation products that may be involved in cartilage catabolism. Consistently, treatment of synovial fibroblasts with HtrA1 or HtrA1-generated fibronectin fragments resulted in the specific induction of matrix metalloprotease 1 and matrix metalloprotease 3 expression, suggesting that HtrA1 contributes to the destruction of extracellular matrix through both direct and indirect mechanisms.Human HtrA1 (L56) is a member of the HtrA 3 (High temperature requirement) family of serine proteases, a well defined group of proteases sharing many of the characteristics associated with bacterial HtrAs (1). Such features include a highly conserved trypsin-like serine protease domain and at least one PDZ domain at the C terminus. In addition, HtrA1 contains an insulin-like growth factor-binding protein domain and a Kazal-type serine protease inhibitor motif at its N terminus (2). Originally identified as a gene down-regulated in SV40-transformed fibroblasts (2), HtrA1 has since been implicated in the modulation of various disease pathologies. Recent reports suggest that HtrA1 plays a protective role in various malignancies because of its tumorsuppressive properties (3-6). Studies have shown that HtrA1 is downregulated in cancerous tissue as compared with normal tissue and that overexpression results in the inhibition of tumor cell growth and proliferation both in vitro and in vivo (5). In contrast to tumor tissue, HtrA1 expression is up-regulated in skeletal muscle of Duchenne muscular dystrophy (7) and in cartilage of osteoarthritic joints (8). Therefore, up-regulation of HtrA1 in osteoarthritic joints may contribute to the development of this debilitating disease.Progressive degradation of components of the extracellular matrix plays an important role in the pathogenesis of arthritic diseases (9, 10). The destruction of the major cartilage components is driven by members of all classes of proteases, including serine proteases, although the matrix metalloproteases (MMPs) are considered to be the primary instigators (11-13). Elevated levels of various MMPs have been identified in the diseased joints of both osteoarthritis (OA) (14 -16) and rheumatoid arthritis (RA) (17) patients, originating primar...
The defining features of the widely conserved HtrA (high temperature requirement) family of serine proteases are the combination of a catalytic protease domain with one or more C-terminal PDZ domains and reversible zymogen activation. Even though HtrAs have previously been implicated in protein quality control and various diseases, including cancer, arthritis, and neuromuscular disorder, the biology of the human family members is not well understood. Our data suggest that HtrA1 is directly involved in the -amyloid pathway as it degrades various fragments of amyloid precursor protein while an HtrA1 inhibitor causes accumulation of A in astrocyte cell culture supernatants. Furthermore, HtrA1 colocalizes with -amyloid deposits in human brain samples. Potential implications in Alzheimer's disease are discussed.protein quality control ͉ amyloid  ͉ C99
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