Structural Analysis of Cholesterol Binding and Sterol Selectivity by ABCG5/G8

Farhat, Danny; Rezaei, Fatemeh; Ristovski, Miliça; Yang, Yidai; Stancescu, Albert; Dzimkova, Lucia; Samnani, Sabrina; Couture, Jean-François; Lee, Jyh-Yeuan

doi:10.1016/j.jmb.2022.167795

Cited by 12 publications

(12 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The poses, parameters and docking data for all three sterols are seen in Tables 3 - 5 . Additionally, both plant sterols are lacking the peak horizontal conformation taken by cholesterol which was resolved in the crystal structure as well as shown in the docking simulation [11] . In the A540F mutant, both plant sterols remain clustered similarly at the bottom of the protein, with the polar heads nearing the intracellular interface.…”

Section: Experimental Design Materials and Methodsmentioning

confidence: 78%

“…The poses were ranked by Van der Waal energy (vdw_energy) values i.e., lower is better. This scoring method was chosen after redocking controls on ABCG2 were conducted [11] . Here, we conducted molecular docking of cholesterol and two plant sterols (stigmasterol and sitosterol) on wild type ABCG5/G8 and mutants ABCG5 A540F as well as ABCG5 Y432F /G8 N564P [1] .…”

Section: Experimental Design Materials and Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Data on structural analysis of cholesterol binding and sterol selectivity by ABCG5/G8

2022

Self Cite

View full text Add to dashboard Cite

Section: Experimental Design Materials and Methodsmentioning

confidence: 78%

Section: Experimental Design Materials and Methodsmentioning

confidence: 99%

Data on structural analysis of cholesterol binding and sterol selectivity by ABCG5/G8

2022

Self Cite

View full text Add to dashboard Cite

“…ATP-binding cassette (ABC) sterol transporters such as ABCG family have a conserved structural motif called phenylalanine highway, where a series of phenylalanines line the dimer interface and enable binding of cholesterol [39]. Like ABCG, these phenylalanine highways have been suggested to exist in other cholesterol binding proteins such as NPC1, PTCH1, and ChUP family of proteins, albeit not always in the dimer interface [39]. In SIDT1, we notice a similar phenylalanine highway - TM11 (D786-L810) and TM1 (K302-R334) are studded with 6 and 5 phenylalanine residues, respectively.…”

Section: Resultsmentioning

confidence: 99%

Structure of the human systemic RNAi defective transmembrane protein 1 (hSIDT1) reveals the conformational flexibility of its lipid binding domain

Navratna,

Kumar,

Rana

et al. 2023

Preprint

View full text Add to dashboard Cite

InC. elegans, the inter-cellular transport of the small non-coding RNA that causes systemic RNA interference (RNAi) is mediated by the transmembrane protein SID1, encoded by thesid1gene in the systemic RNA interference-defective (sid) loci. SID1 shares remarkable structural and sequence similarity with cholesterol uptake protein 1 (CHUP1), and they are classified together as members of the cholesterol uptake family (ChUP). Although systemic RNAi is not an evolutionarily conserved process, thesidgene products are found across the animal kingdom, suggesting a potential for the existence of other novel gene regulatory mechanisms mediated by small non-coding RNAs. Human homologs ofsidgene products – hSIDT1 and hSIDT2 – are believed to mediate contact-dependent lipophilic small non-coding dsRNA transport. Here, we report the structure of recombinant full-length human SIDT1. We find that the extra-cytosolic domain (ECD) of hSIDT1 adopts a double jelly roll fold, and the transmembrane domain (TMD) exists as two modules – a flexible lipid binding domain (LBD) and a rigid TMD core. Our structural analyses provide insights into the potential role of the lipid binding domain in the function of hSIDT1 and other cholesterol uptake (ChUP) family members.

show abstract

“…Of note, and surprisingly, the shape and size of the ABCG2 translocation path is different from other ABCGs and even the conserved yeast PDRs. The central cavity of the G5/G8 heterodimer is asymmetric and compressed, and the upper cavity is less well defined as an open cavity (PDB ID: 5DO7, 7R8A, 7R8B, 8CUB) 25,59,60 . This might be because ABCG5/ABCG8 is a heterodimeric transport complex.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, aromatic side chains often play important gating mechanisms in ABC transporters, including P-gp 67,68 , bacterial manganese importer (PsaBC) 69 , Streptomyces peucetius (DrrAB) 70 , RND transporters 71 , as well as aromatic pores in the MCE protein family 72 . Phenylalanines also form a hydrophobic cluster in the core of ABCG1 62 , as well as ABCG5/ABCG8 60 . Since, ABCG1 and ABCG4 are lipid pumps, phenylalanines are likely to fulfil an essential mechanistic binding step rather than affecting substrate selectivity.…”

Section: Discussionmentioning

confidence: 99%

The Human ABCG2 Transporter Relies on a Triple-Gated Translocation Channel for Multidrug Efflux

Kuchler,

Khunweeraphong

2024

Preprint

View full text Add to dashboard Cite

The human ABCG2 drug transporter plays essential roles in physiological detoxification across barrier tissues and in anticancer multidrug resistance. However, the routes for drug extrusion and gating mechanisms remain elusive. Here, we demonstrate that the inner core of the ABCG2 structure holds two cavities that are delimited by three gates, revealing a possible substrate translocation channel within the transporter core. Drugs can enter via an intracellular entry gate to become trapped in the voluminous central cavity. The cavity is surrounded by a cluster of three conserved phenylalanines providing aromatic rings for a “clamp-push-seal” motion to ensure unidirectional substrate movement towards the upper cavity. Two ABCG2-unique residues, T435 and N436, are the critical discriminators for substrate selectivity prior moving through the valve gate. The dynamic outer cavity is covered by the extracellular lid architecture functioning as the final gate to mediate drug extrusion. This work unravels unprecedented mechanistic details about critical gating steps, including the order of events that drive ABCG2-mediated drug efflux.

show abstract

Structural Analysis of Cholesterol Binding and Sterol Selectivity by ABCG5/G8

Cited by 12 publications

References 71 publications

Data on structural analysis of cholesterol binding and sterol selectivity by ABCG5/G8

Data on structural analysis of cholesterol binding and sterol selectivity by ABCG5/G8

Structure of the human systemic RNAi defective transmembrane protein 1 (hSIDT1) reveals the conformational flexibility of its lipid binding domain

The Human ABCG2 Transporter Relies on a Triple-Gated Translocation Channel for Multidrug Efflux

Contact Info

Product

Resources

About