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  • Title: Kinetics of Fc epsilon RI dimer formation by specific monoclonal antibodies on mast cells.
    Author: Schweitzer-Stenner R, Ortega E, Pecht I.
    Journal: Biochemistry; 1994 Jul 26; 33(29):8813-25. PubMed ID: 8038173.
    Abstract:
    Clustering of the type I receptor for Fc epsilon domains constitutes the signal initiation leading to mast cell secretory response. In order to characterize the relationship between the lifetime of clustered Fc epsilon receptors and the cellular response we have studied the rates of association and dissociation of monoclonal, IgG class antibodies (mAbs) specific for the alpha-subunit of type 1 receptor for IgE (Fc epsilon RI) (designated as F4, J17, and H10) to and from this receptor on live rat mucosa-type mast cells (line RBL-2H3) were measured at three different temperatures (25, 15, and 4 degrees C). These antibodies dimerize the Fc epsilon RI on these cells and induce their secretion, thus providing clear evidence that Fc epsilon receptor dimers are sufficient for the stimulus [Ortega et al. (1988), EMBO J. 7, 4101]. Marked differences in the response to the different mAbs have been explained in terms of possible orientational constraints imposed by them on the Fc epsilon receptor dimers. Interaction kinetics between the Fab fragments of these mAbs and the Fc epsilon RI have previously been measured and found to be best fitted by a two-reaction-step model involving a conformational transition from a low-affinity (l) to a high-affinity (h) state of the receptor-ligand complex [Ortega et al. (1991) Biochemistry 30, 3473]. Analysis of the interaction kinetics between the corresponding intact mAbs and the Fc epsilon RI therefore requires consideration of this 1-->h transition for both complexes involved, namely, the monomeric Fc epsilon RI-mAb and the dimeric Fc epsilon RI-mAb-Fc epsilon RI complexes. This was done by assuming the involvement of the following Fc epsilon RI dimer species: all 1- or h-state dimers Dll and Dhh and a hybrid Dlh with one receptor in the l state and the other in the h state. A self-consistent set of rate constants was derived by fitting the experimental results to this model. At 25 degrees C the all-h-state dimers Dhh turned out to be preferentially stabilized, probably by interaction with other cellular components. Different dimer formation rates were observed for each of the three mAbs, indicating that the dimer distribution among different states is determined by the individual epitope-binding site combination and also by the geometry of the respective complexes.(ABSTRACT TRUNCATED AT 400 WORDS)
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