ERp44 quality control and IgM polymerization. IgM monomers are assembled into polymers in the early secretory pathway with the help of the hexameric lectin ERGIC-53. IgM polymers are released from ERGIC-53 in the Golgi and can then be secreted. In the Golgi, ERp44—in an open conformation thanks to the slightly acidic pH—interacts with unassembled IgM subunits exposing the C-terminal cysteine 575 in the SH conformation (inset (a)): the covalent binding between ERp44’s active site cysteine 29 and the IgM subunits requires an oxidative power whose source is still unknown. The interaction with the cargo favors the exposure of ERp44’s C-terminal RDEL for binding to the KDEL receptor and the complex KDEL receptor-ERp44-cargo (IgM H2L2 “monomer”) is then transported back to the ER. Here, a reducing power disentangles the disulfide bond between ERp44 and the IgM “monomer.” The neutral pH in the ER, which also inhibits the KDEL receptor activity, now stabilizes ERp44 in a more closed conformation (inset (b)). Keeping ERp44 in a closed conformation in the ER likely is important to avoid that ERp44 interacts with subunits that productively take part in the polymerization process.
