Summary

A prerequisite for antibody secretion and function is the assembly into a defined quaternary structure, composed of two heavy and two light chains for IgG. Unassembled heavy chains are actively retained in the endoplasmic reticulum (ER) until they associate with light chains. Our mechanistic analysis of this critical quality control step revealed that, unlike all other antibody domains studied, the CH1 domain of the murine IgG1 heavy chain is an intrinsically disordered protein in isolation. It adopts the typical immunoglobulin fold only upon interaction with its cognate partner, the CL domain. Structure formation proceeds via a trapped intermediate, can be accelerated by the ER-specific peptidyl-prolyl isomerase cyclophilin B, and is modulated by the molecular chaperone BiP. BiP recognizes incompletely folded states of the CH1 domain and competes for binding to the CL domain. In vivo experiments demonstrate that requirements identified for folding the CH1 domain in vitro, including association with a folded CL domain and isomerization of a conserved proline residue, are essential for antibody assembly and secretion in the cell