Structural insights into functional lipid-protein interactions in secondary transporters

Structural evidences with functional corroborations have revealed distinct features of lipid-protein interactions especially in channels and receptors. Many membrane embedded transporters are also known to require specific lipids for their functions and for some of them cellular and biochemical data suggest tight regulation by the lipid bilayer. However, molecular details on lipid-protein interactions in transporters are sparse since lipids are either depleted from the detergent solubilized transporters in three-dimensional crystals or not readily resolved in crystal structures. Nevertheless the steady increase in the progress of transporter structure determination contributed more examples of structures with resolved lipids.

This review gives an overview on transporter structures in complex with lipids reported to date and discusses commonly encountered difficulties in the identification of functionally significant lipid-protein interactions based on those structures and functional in vitro data. Recent structures provided molecular details into regulation mechanism of transporters by specific lipids. The review highlights common findings and conserved patterns for distantly related transporter families to draw a more general picture on the regulatory role of lipid-protein interactions.

Several common themes of the manner in which lipids directly influence membrane-mediated folding, oligomerization and structure stability can be found. Especially for LeuT-like fold transporters similarities in structurally resolved lipid-protein interactions suggest a common way in which transporter conformations are affected by lipids even in evolutionarily distinct transporters. Lipids appear to play an additional role as joints mechanically reinforcing the inverted repeat topology, which is a major determinant in the alternating access mechanism of secondary transporters.

This review brings together and adds to the repertoire of knowledge on lipid-protein interactions of functional significance presented in structures of membrane transporters. Knowledge of specific lipid-binding sites and modes of lipid influence on these proteins not only accomplishes the molecular description of transport cycle further, but also sheds light into localization dependent differences of transporter function. This article is part of a Special Issue entitled Structural biochemistry and biophysics of membrane proteins.