Structure and mechanism of an active lipid-linked oligosaccharide flippase

Camilo Perez, Sabina Gerber, Jérémy Boilevin, Monika Bucher, Tamis Darbre, Markus Aebi, Jean-Louis Reymond and Kaspar P. Locher ()
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Camilo Perez: Institute of Molecular Biology and Biophysics, ETH Zürich
Sabina Gerber: Institute of Molecular Biology and Biophysics, ETH Zürich
Jérémy Boilevin: University of Berne
Monika Bucher: Institute of Molecular Biology and Biophysics, ETH Zürich
Tamis Darbre: University of Berne
Markus Aebi: Institute of Microbiology, ETH Zürich
Jean-Louis Reymond: University of Berne
Kaspar P. Locher: Institute of Molecular Biology and Biophysics, ETH Zürich

Nature, 2015, vol. 524, issue 7566, 433-438

Abstract: Abstract The flipping of membrane-embedded lipids containing large, polar head groups is slow and energetically unfavourable, and is therefore catalysed by flippases, the mechanisms of which are unknown. A prominent example of a flipping reaction is the translocation of lipid-linked oligosaccharides that serve as donors in N-linked protein glycosylation. In Campylobacter jejuni, this process is catalysed by the ABC transporter PglK. Here we present a mechanism of PglK-catalysed lipid-linked oligosaccharide flipping based on crystal structures in distinct states, a newly devised in vitro flipping assay, and in vivo studies. PglK can adopt inward- and outward-facing conformations in vitro, but only outward-facing states are required for flipping. While the pyrophosphate-oligosaccharide head group of lipid-linked oligosaccharides enters the translocation cavity and interacts with positively charged side chains, the lipidic polyprenyl tail binds and activates the transporter but remains exposed to the lipid bilayer during the reaction. The proposed mechanism is distinct from the classical alternating-access model applied to other transporters.

Date: 2015
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DOI: 10.1038/nature14953

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