Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 2 de 2
Filter
Add more filters










Database
Language
Publication year range
1.
Nature ; 630(8016): 501-508, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38778100

ABSTRACT

Human feline leukaemia virus subgroup C receptor-related proteins 1 and 2 (FLVCR1 and FLVCR2) are members of the major facilitator superfamily1. Their dysfunction is linked to several clinical disorders, including PCARP, HSAN and Fowler syndrome2-7. Earlier studies concluded that FLVCR1 may function as a haem exporter8-12, whereas FLVCR2 was suggested to act as a haem importer13, yet conclusive biochemical and detailed molecular evidence remained elusive for the function of both transporters14-16. Here, we show that FLVCR1 and FLVCR2 facilitate the transport of choline and ethanolamine across the plasma membrane, using a concentration-driven substrate translocation process. Through structural and computational analyses, we have identified distinct conformational states of FLVCRs and unravelled the coordination chemistry underlying their substrate interactions. Fully conserved tryptophan and tyrosine residues form the binding pocket of both transporters and confer selectivity for choline and ethanolamine through cation-π interactions. Our findings clarify the mechanisms of choline and ethanolamine transport by FLVCR1 and FLVCR2, enhance our comprehension of disease-associated mutations that interfere with these vital processes and shed light on the conformational dynamics of these major facilitator superfamily proteins during the transport cycle.


Subject(s)
Choline , Ethanolamine , Membrane Transport Proteins , Humans , Binding Sites , Biological Transport , Cations/chemistry , Cations/metabolism , Cell Membrane/metabolism , Cell Membrane/chemistry , Choline/metabolism , Choline/chemistry , Ethanolamine/metabolism , Ethanolamine/chemistry , Membrane Transport Proteins/metabolism , Membrane Transport Proteins/chemistry , Membrane Transport Proteins/genetics , Models, Molecular , Protein Conformation , Receptors, Virus/metabolism , Receptors, Virus/chemistry , Substrate Specificity , Tryptophan/metabolism , Tryptophan/chemistry , Tyrosine/metabolism , Tyrosine/chemistry , Mutation
2.
Int J Mol Sci ; 24(1)2022 Dec 28.
Article in English | MEDLINE | ID: mdl-36613930

ABSTRACT

The subfamily-G ATP-binding cassette (ABCG) transporters play important roles in regulating cholesterol homeostasis. Recent progress in the structural data of ABCG1 and ABCG5/G8 disclose putative sterol binding sites that suggest the possible cholesterol translocation pathway. ABCG1 and ABCG5/G8 share high similarity in the overall molecular architecture, and both transporters appear to use several unique structural motifs to facilitate cholesterol transport along this pathway, including the phenylalanine highway and the hydrophobic valve. Interestingly, ABCG5/G8 is known to transport cholesterol and phytosterols, whereas ABCG1 seems to exclusively transport cholesterol. Ligand docking analysis indeed suggests a difference in recruiting sterol molecules to the known sterol-binding sites. Here, we further discuss how the different and shared structural features are relevant to their physiological functions, and finally provide our perspective on future studies in ABCG cholesterol transporters.


Subject(s)
Cholesterol , Lipoproteins , Lipoproteins/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 5/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 5/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 8/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 8/metabolism , Cholesterol/metabolism , Sterols/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL
...