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<jats:title>Abstract</jats:title><jats:p>The endoplasmic reticulum (ER) is the main site of protein synthesis in eukaryotic cells and requires a high concentration of luminal chaperones to function. During protein synthesis, ER luminal chaperones are swept along the secretory pathway and must be retrieved to maintain cell viability. ER protein retrieval is achieved by the KDEL receptor, which recognises a C-terminal Lys-Asp-Glu-Leu (KDEL) sequence. Recognition of ER proteins by the KDEL receptor is pH dependent, with binding occurring under acidic conditions in the Golgi and release under conditions of higher pH in the ER. Recent crystal structures of the KDEL receptor in the apo and peptide bound state suggested that peptide binding drives the formation of a short-hydrogen bond that locks the KDEL sequence in the receptor and activates the receptor for COPI binding in the cytoplasm. Using quantum mechanical calculations we demonstrate that the strength of this short hydrogen bond is reinforced following protonation of a nearby histidine, linking receptor protonation to high affinity peptide binding. Protonation also controls the wetting of a cavity adjacent to the peptide binding site, leading to a conformational change that ultimately allows the complex to be recognized by the COPI system.</jats:p>

Original publication

DOI

10.1101/2020.07.18.209858

Type

Journal article

Journal

BioRxiv

Publisher

Cold Spring Harbor Laboratory

Publication Date

20/07/2020