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

DOI: 10.7554/eLife.68380

Authors: Andreas Gerondopoulos (University of Oxford) , Philipp Braeuer (University of Oxford) , Tomoaki Sobajima (University of Oxford) , Zhiyi Wu (University of Oxford) , Joanne L. Parker (University of Oxford) , Philip Biggin (University of Oxford) , Francis A Barr (University of Oxford) , Simon Newstead (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Elife , VOL 10

State: Published (Approved)
Published: June 2021
Diamond Proposal Number(s): 23459

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 10-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.

Journal Keywords: Cell Biology; Golgi; endoplasmic reticulum; cargo receptor; KDEL; HDEL

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 08/07/2021 09:07

Documents:
elife-68380-v2.pdf

Discipline Tags:

Biochemistry Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)