Structure of the WD40 domain of SCAP from fission yeast reveals the molecular basis for SREBP recognition

Cell Research
Xin GongNieng Yan

Abstract

The sterol regulatory element-binding protein (SREBP) and SREBP cleavage-activating protein (SCAP) are central players in the SREBP pathway, which control the cellular lipid homeostasis. SCAP binds to SREBP through their carboxyl (C) domains and escorts SREBP from the endoplasmic reticulum to the Golgi upon sterol depletion. A conserved pathway, with the homologues of SREBP and SCAP being Sre1 and Scp1, was identified in fission yeast Schizosaccharomyces pombe. Here we report the in vitro reconstitution of the complex between the C domains of Sre1 and Scp1 as well as the crystal structure of the WD40 domain of Scp1 at 2.1 Å resolution. The structure reveals an eight-bladed β-propeller that exhibits several distinctive features from a canonical WD40 repeat domain. Structural and biochemical characterization led to the identification of two Scp1 elements that are involved in Sre1 recognition, an Arg/Lys-enriched surface patch on the top face of the WD40 propeller and a 30-residue C-terminal tail. The structural and biochemical findings were corroborated by in vivo examinations. These studies serve as a framework for the mechanistic understanding and further functional characterization of the SREBP and SCAP proteins in fission yea...Continue Reading

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Citations

Mar 20, 2016·Chemistry and Physics of Lipids·Vicky HoweAndrew J Brown
Jun 25, 2013·Cell Metabolism·Erin CurrieRobert V Farese
Aug 30, 2017·Nature Reviews. Endocrinology·Hitoshi Shimano, Ryuichiro Sato
Jul 14, 2020·Bioscience, Biotechnology, and Biochemistry·Ryuichiro Sato
Oct 28, 2020·Proceedings of the National Academy of Sciences of the United States of America·Daniel L KoberArun Radhakrishnan
Feb 19, 2021·The Journal of Experimental Medicine·Xueli BianZhimin Lu

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Methods Mentioned

BETA
sequence-based prediction
pull-down
ion-exchange
size-exclusion chromatography
PCR

Software Mentioned

BUCCANEER
SHELXE
PHENIX
CCP4
PHASER
COOT

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