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Mapping the Major Interaction Between Binding Protein and Ig Light Chains to Sites Within the Variable Domain¹

David P. Davis^2,*,, Ritu Khurana^2,3,*,, Stephen Meredith^*, Fred J. Stevens and Yair Argon^4,*,

^* Department of Pathology and Committee on Immunology, University of Chicago, Chicago, IL 60637; and Center for Mechanistic Biology and Biotechnology, Argonne National Laboratory, Argonne, IL 60439 ⁶S. Aviel et al., submitted for publication.

Newly synthesized Ig chains are known to interact in vivo with the binding protein (BiP), a major peptide-binding chaperone in the endoplasmic reticulum. The predominant interactions between the light chain and BiP are observed early in the folding pathway, when the light chain is either completely reduced, or has only one disulfide bond. In this study, we describe the in vitro reconstitution of BiP binding to the variable domain of light chains (V_L). Binding of deliberately unfolded V_L was dramatically more avid than that of folded V_L, mimicking the interaction in vivo. Furthermore, V_L binding was inhibited by addition of ATP, was competed with excess unlabeled V_L, and was demonstrated with several different V_L proteins. Using this assay, peptides derived from the V_L sequence were tested experimentally for their ability to bind BiP. Four peptides from both ß sheets of V_L were shown to bind BiP specifically, two with significantly higher affinity. As few as these two peptide sites, one from each ß sheet of V_L, are sufficient to explain the association of BiP with the entire light chain. These results suggest how BiP directs the folding of Ig in vivo and how it may be used in shaping the B cell repertoire.

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