Structural basis for sterol sensing by Scap and Insig

Yan, Renhong; Cao, Pingping; Song, Wenchao; Li, Yaning; Wang, Tongtong; Qian, Hui‐Fen; Yan, Chuangye; Yan, Nieng

doi:10.1016/j.celrep.2021.109299

Cited by 19 publications

(32 citation statements)

References 60 publications

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“…As analyzed above, GLUT4, which has a two-fold pseudo symmetry in the membrane and lacks a bulky soluble domain, presented many challenges for cryo-EM analysis. Our previous work with MCT1 26 and the Scap/Insig-2 complex 22 , 23 suggests that the size of the micelles could have a direct impact on 2D and 3D classifications. We therefore set out to screen for detergents that gave rise to the best protein signal (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Details can be found in Methods. Following our previously developed “guided multi-reference 3D classification” and “seed”-facilitated 3D classification strategy 22 , 23 , 26 , 29 , the resolutions of GLUT4 embedded in the LMNG/CHS micelles and nanodiscs both reached 3.3 Å after several rounds of 3D classification and refinement by cryoSPARC (Fig. 1e , Supplementary Figs.…”

Section: Resultsmentioning

confidence: 99%

“…One of our research interests has been to develop and optimize methods for solving high-resolution structures of small membrane proteins using advanced technology of cryo-EM. We started with proteins containing relatively flexible soluble domains, such as the monocarboxylate transporter MCT1 26 and the complex of Scap and Insig-2 22 , 23 . Encouraged by these successful attempts, we took a direct assault on human GLUT4.…”

Section: Introductionmentioning

confidence: 99%

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Cryo-EM structure of human glucose transporter GLUT4

Yuan

Kong

et al. 2022

Nat Commun

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GLUT4 is the primary glucose transporter in adipose and skeletal muscle tissues. Its cellular trafficking is regulated by insulin signaling. Failed or reduced plasma membrane localization of GLUT4 is associated with diabetes. Here, we report the cryo-EM structures of human GLUT4 bound to a small molecule inhibitor cytochalasin B (CCB) at resolutions of 3.3 Å in both detergent micelles and lipid nanodiscs. CCB-bound GLUT4 exhibits an inward-open conformation. Despite the nearly identical conformation of the transmembrane domain to GLUT1, the cryo-EM structure reveals an extracellular glycosylation site and an intracellular helix that is invisible in the crystal structure of GLUT1. The structural study presented here lays the foundation for further mechanistic investigation of the modulation of GLUT4 trafficking. Our methods for cryo-EM analysis of GLUT4 will also facilitate structural determination of many other small size solute carriers.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cryo-EM structure of human glucose transporter GLUT4

Yuan

Kong

et al. 2022

Nat Commun

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“…The cryo-electron microscopic (cryo-EM) structure (PDB: 7ETW) of the dimer is shown in Fig. 1 (Yan et al 2021a ); this structure is more complete than the other two published structures for the dimer (PDB: 6M49, 7LKF) (Kober et al 2021 ; Yan et al 2021b ). Scap and Insig contain eight and six transmembrane (TM) helices respectively.…”

Section: Introductionmentioning

confidence: 92%

The role of cholesterol binding in the control of cholesterol by the Scap–Insig system

Lee

2022

Eur Biophys J

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Scap and Insig, two proteins embedded in the membrane of the endoplasmic reticulum (ER), regulate the synthesis of cholesterol in animal cells by forming a dimer in the presence of high concentrations of cholesterol. Cryo-electron microscopic structures for the Scap–Insig dimer show a sterol-binding site at the dimer interface, but none of the structures include cholesterol itself. Here, a molecular docking approach developed to characterise cholesterol binding to the transmembrane (TM) regions of membrane proteins is used to characterise cholesterol binding to sites on the TM surface of the dimer and to the interfacial binding site. Binding of cholesterol is also observed at sites on the extra-membranous luminal domains of Scap, but the properties of these sites suggest that they will be unoccupied in vivo. Comparing the structure of Scap in the dimer with that predicted by AlphaFold for monomeric Scap suggests that dimer formation could result in relocation of TM helix 7 of Scap and of the loop between TM6 and 7, and that this could be the key change on Scap that signals that there is a high concentration of cholesterol in the ER.

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“…In the process, SCAP and INSIG1/2 are the core sterol sensors that control the SREBP pathway. Except for sterol, the space configuration and posttranslational modifications such as phosphorylation and glycosylation also affect functions of these proteins (21)(22)(23)(24). However, the association of ASGR1 with the SREBP pathway remains unknown, and it needs further investigation to improve our understanding of lipid homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Hypomorphic ASGR1 modulates lipid homeostasis via INSIG1-mediated SREBP signaling suppression

Xu¹,

Tao²,

Yu³

et al. 2021

JCI Insight

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Structural basis for sterol sensing by Scap and Insig

Cited by 19 publications

References 60 publications

Cryo-EM structure of human glucose transporter GLUT4

Cryo-EM structure of human glucose transporter GLUT4

The role of cholesterol binding in the control of cholesterol by the Scap–Insig system

Hypomorphic ASGR1 modulates lipid homeostasis via INSIG1-mediated SREBP signaling suppression

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