Clustering for the kill
Cluster of differentiation 20 (CD20) is a membrane protein that defines most B cell populations and is the target of therapeutic antibodies to treat malignancies and autoimmune disorders. The structure of CD20 bound to the antibody rituximab that activates the complement system (a cascade of enzymes that punch holes in their target to kill them) to kill B cells. CD20 forms a dimer (two molecules) and each monomer (single entity in this case one molecule of CD20) binds one rituximab antigen-binding fragment (Fab) (one arm of an antibody molecule). The compact packing between Fab arms and CD20 gives rise to circular assemblies with a diameter similar to that of antibody hexamers (five antibody molecules) known to recruit the first component of the complement cascade this is called C1q.
Previous reports have suggested the possibility that CD20 may form a plasma membrane ion channel, but the analyses reveal no plausible ion permeation pathway through the monomeric CD20 protomer or along the dimeric packing interface. Therefore, CD20 is unlikely to directly function asan ion channel
They show that a number of antibody molecules may bind the CD20 receptors that cluster as two molecules of CD20 and this may allow the complement to (in red below) to be activated.
Structure of CD20 in complex with the therapeutic monoclonal antibody rituximab. Rougé L, Chiang N, Steffek M, Kugel C, Croll TI, Tam C, Estevez A, Arthur CP, Koth CM, Ciferri C, Kraft E, Payandeh J, Nakamura G, Koerber JT, Rohou A. Science. 2020;367(6483):1224-1230.
Cluster of differentiation 20 (CD20) is a B cell membrane protein that is targeted by monoclonal antibodies for the treatment of malignancies and autoimmune disorders but whose structure and function are unknown. Rituximab (RTX) has been in clinical use for two decades, but how it activates complement to kill B cells remains poorly understood. We obtained a structure of CD20 in complex with RTX, revealing CD20 as a compact double-barrel dimer bound by two RTX antigen-binding fragments (Fabs), each of which engages a composite epitope and an extensive homotypic Fab:Fab interface. Our data suggest that RTX cross-links CD20 into circular assemblies and lead to a structural model for complement recruitment. Our results further highlight the potential relevance of homotypic Fab:Fab interactions in targeting oligomeric cell-surface mark