Crystal structure of the human sterol transporter ABCG5/ABCG8.

• Autores: Jyh-Yeuan Lee, Lisa N. Kinch, Dominika M. Borek, Jin Wang, Junmei Wang, Ina L. Urbatsch, Xiao-Song Xie
• Localización: Nature: International weekly journal of science, ISSN 0028-0836, Vol. 533, Nº 7604, 2016, págs. 561-564
• Idioma: inglés
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• Resumen

  • ATP binding cassette (ABC) transporters play critical roles in maintaining sterol balance in higher eukaryotes. The ABCG5/ABCG8 heterodimer (G5G8) mediates excretion of neutral sterols in liver and intestines 1,2,3,4,5. Mutations disrupting G5G8 cause sitosterolaemia, a disorder characterized by sterol accumulation and premature atherosclerosis. Here we use crystallization in lipid bilayers to determine the X-ray structure of human G5G8 in a nucleotide-free state at 3.9 A resolution, generating the first atomic model of an ABC sterol transporter. The structure reveals a new transmembrane fold that is present in a large and functionally diverse superfamily of ABC transporters. The transmembrane domains are coupled to the nucleotide-binding sites by networks of interactions that differ between the active and inactive ATPases, reflecting the catalytic asymmetry of the transporter. The G5G8 structure provides a mechanistic framework for understanding sterol transport and the disruptive effects of mutations causing sitosterolaemia.