A signal capture and proofreading mechanism for the KDEL-receptor explains selectivity and dynamic range in ER retrieval

ER proteins of widely differing abundance are retrieved from the Golgi by KDEL-receptor. Abundant tend to have KDEL rather than HDEL signals, whereas ADEL and DDEL not used in most organisms. Here, we explore mechanism selective retrieval signal capture KDEL-receptor how binds with 10-fold higher affinity KDEL. Our results show carboxyl-terminus moves along a ladder arginine residues as it enters binding pocket receptor. Gatekeeper D50 E117 at entrance this exclude sequences. D50N/E117Q mutation human KDEL-receptors changes selectivity DDEL. However, further analysis HDEL, KDEL, RDEL-bound receptor structures shows that differences explained interactions between variable −4 H/K/R position W120, or E117. Together, these findings explain selectivity, variants increase dynamic range support efficient low high proteins.