A signal capture and proofreading mechanism for the KDEL-receptor explains selectivity and dynamic range in ER retrieval
- University of Oxford, United Kingdom
Abstract
ER proteins of widely differing abundance are retrieved from the Golgi by the KDEL-receptor. Abundant ER proteins tend to have KDEL rather than HDEL signals, whereas ADEL and DDEL are not used in most organisms. Here, we explore the mechanism of selective retrieval signal capture by the KDEL-receptor and how HDEL binds with ten-fold higher affinity than KDEL. Our results show the carboxyl-terminus of the retrieval signal moves along a ladder of arginine residues as it enters the binding pocket of the receptor. Gatekeeper residues D50 and E117 at the entrance of this pocket exclude ADEL and DDEL sequences. D50N/E117Q mutation of human KDEL-receptors changes the selectivity to ADEL and DDEL. However, further analysis of HDEL, KDEL and RDEL-bound receptor structures shows that affinity differences are explained by interactions between the variable -4 H/K/R position of the signal and W120, rather than D50 or E117. Together, these findings explain KDEL-receptor selectivity, and how signal variants increase dynamic range to support efficient ER retrieval of low and high abundance proteins.
Data availability
Atomic coordinates for the models have been deposited in the Protein Data Bank (PDB) under accession codes 6Y7V and 6ZXR.Data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1, 1Sup1, 1Sup2, 2, 3, 3Sup1, 4, 4Sup1, 6, 6Sup1, 6Sup2, 7, and 7Sup1.
Article and author information
Author details
Francis A Barr Ph.D.
Funding
Wellcome Trust (219531/Z/19/Z,203741/Z/16/A and 109133/Z/15/A)
- Zhiyi Wu
Engineering and Physical Sciences Research Council (EP/R029407/1)
- Andreas Gerondopoulos
- Philipp Bräuer
- Tomoaki Sobajima
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Gerondopoulos et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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