Structural evidence for functional lipid interactions in the betaine transporter BetP

Bilayer lipids contribute to the stability of membrane transporters and are crucially involved in their proper functioning. However, the molecular knowledge of how surrounding lipids affect membrane transport is surprisingly limited and despite its general importance is rarely considered in the molecular description of a transport mechanism. One reason is that only few atomic resolution structures of channels or transporters reveal a functional interaction with lipids, which are difficult to detect in X‐ray structures per se. Overcoming these difficulties, we report here on a new structure of the osmotic stress‐regulated betaine transporter BetP in complex with anionic lipids. This lipid‐associated BetP structure is important in the molecular understanding of osmoregulation due to the strong dependence of activity regulation in BetP on the presence of negatively charged lipids. We detected eight resolved palmitoyl‐oleoyl phosphatidyl glycerol (PG) lipids mimicking parts of the membrane leaflets and interacting with key residues in transport and regulation. The lipid–protein interactions observed here in structural detail in BetP provide molecular insights into the role of lipids in osmoregulated secondary transport.