Structural basis for pH-dependent retrieval of ER proteins from the Golgi by the KDEL receptor

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Science  08 Mar 2019:
Vol. 363, Issue 6431, pp. 1103-1107
DOI: 10.1126/science.aaw2859

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Crystal structure of the KDEL receptor

Eukaryotic cells concentrate chaperones in the lumen of the endoplasmic reticulum (ER). These chaperones can be swept along the secretory pathway to the Golgi apparatus, from where they must be returned. For 20 years, cell biologists have known the identity of the KDEL (Lys-Asp-Glu-Leu) receptor responsible for this process, but the molecular basis for its function has remained elusive. Now, Bräuer et al. present crystal structures of the KDEL receptor, in both the apo ER state and KDEL retrieval signal–bound Golgi state. Comparisons of these two states identify the conformational switch that exposes the ER retrieval motif. The authors recapitulated the binding and release cycle of the receptor using purified components, confirming that the receptor is the minimal component required to bind KDEL ligands in the Golgi.

Science, this issue p. 1103


Selective export and retrieval of proteins between the endoplasmic reticulum (ER) and Golgi apparatus is indispensable for eukaryotic cell function. An essential step in the retrieval of ER luminal proteins from the Golgi is the pH-dependent recognition of a carboxyl-terminal Lys-Asp-Glu-Leu (KDEL) signal by the KDEL receptor. Here, we present crystal structures of the chicken KDEL receptor in the apo ER state, KDEL-bound Golgi state, and in complex with an antagonistic synthetic nanobody (sybody). These structures show a transporter-like architecture that undergoes conformational changes upon KDEL binding and reveal a pH-dependent interaction network crucial for recognition of the carboxyl terminus of the KDEL signal. Complementary in vitro binding and in vivo cell localization data explain how these features create a pH-dependent retrieval system in the secretory pathway.

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