An Unfolded C_H1 Domain Controls the Assembly and Secretion of IgG Antibodies

A prerequisite for antibody secretion and function is their 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). Here, we show that the C_H1 domain of the heavy chain is intrinsically disordered in vitro, which sets it apart from other antibody domains. It folds only upon interaction with the light-chain C_L domain. Structure formation proceeds via a trapped intermediate and can be accelerated by the ER-specific peptidyl-prolyl isomerase cyclophilin B. The molecular chaperone BiP recognizes incompletely folded states of the C_H1 domain and competes for binding to the C_L domain. In vivo experiments demonstrate that requirements identified for folding the C_H1 domain in vitro, including association with a folded C_L domain and isomerization of a conserved proline residue, are essential for antibody assembly and secretion in the cell.