Crystal structure of human ERp44 shows a dynamic functional modulation by its carboxy-terminal tail

Abstract

ERp44 mediates thiol-dependent retention in the early secretory pathway, forming mixed disulphides with substrate proteins through its conserved CRFS motif. Here, we present its crystal structure at a resolution of 2.6 Å. Three thioredoxin domains-a, b and b′-are arranged in a clover-like structure. A flexible carboxy-terminal tail turns back to the b′ and a domains, shielding a hydrophobic pocket in domain b′ and a hydrophobic patch around the CRFS motif in domain a. Mutational and functional studies indicate that the C-terminal tail gates the CRFS area and the adjacent hydrophobic pocket, dynamically regulating protein quality control.