PT  - JOURNAL ARTICLE
AU  - Andreas Gerondopoulos
AU  - Philipp Bräuer
AU  - Tomoaki Sobajima
AU  - Zhiyi Wu
AU  - Joanne L. Parker
AU  - Philip C. Biggin
AU  - Francis A. Barr
AU  - Simon Newstead
TI  - A baton-relay and proofreading mechanism for selective ER retrieval signal capture by the KDEL receptor
AID  - 10.1101/2021.03.21.436307
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.03.21.436307
4099  - http://biorxiv.org/content/early/2021/03/23/2021.03.21.436307.short
4100  - http://biorxiv.org/content/early/2021/03/23/2021.03.21.436307.full
AB  - The KDEL-retrieval pathway captures escaped ER proteins with a KDEL or variant C-terminal signal at acidic pH in the Golgi and releases them at neutral pH in the ER. To address the mechanism of signal binding and the molecular basis for differences in signal affinity, we determined the HDEL and RDEL bound structures of the KDEL-receptor. Affinity differences are explained by interactions between the variable −4 position of the signal and W120, whereas initial capture of retrieval signals by their carboxyl-terminus is mediated by a baton-relay mechanism involving a series of conserved arginine residues in the receptor. This explains how the signal is first captured and then pulled into the binding cavity. During capture, retrieval signals undergo a selective proofreading step involving two gatekeeper residues D50 and E117 in the receptor. These mechanisms operate upstream of the pH-dependent closure of the receptor and explain the selectivity of the KDEL-retrieval pathway.Competing Interest StatementThe authors have declared no competing interest.