Fig. 6

Zn²⁺-dependent and pH-dependent regulation of ERp44 for efficient client retention in the early secretory pathway. Proposed working model of the Zn²⁺-dependent and pH-dependent ERp44 cycle operating for protein quality control in the ESP. In the ERGIC and cis-Golgi, ERp44 is in equilibrium between monomeric metal-free, monomeric Zn²⁺-bound, and Zn²⁺-mediated homodimeric conformations. Upon the arrival of a client like Ero1α, the equilibrium is shifted in favor of the monomeric state with the C-tail opened, favoring the exposure of the RDEL motif. Thus, the ERp44–client complex is promptly bound by KDELR and therewith transported back to the ER. The lower Zn²⁺ concentration in the neutral ER likely promotes the dissociation of the ERp44–client complexes, allowing another ERp44 cycle through the ESP