New insights into the structures of secondary transporters

Abstract

In recent years a variety of bacterial membrane protein structures have been solved at atomic resolution, giving us our first insights into what these proteins look like in the membrane and how they might carry out their function. However, although ubiquitous in nature, there are still no high-resolution structures of secondary transporters (electrochemical-potential-driven porters). Although this still remains the case, two recent publications [1.xProjection structure at 8A resolution of the melibiose permease, an Na-sugar co-transporter from Escherichia coli. Hacksell, I. et al. EMBO J. 2002; 21: 3569–3574CrossRef | Scopus (39)See all References, 2.xThree-dimensional structure of a bacterial oxalate transporter. Hirai, T. et al. Nat. Struct. Biol. 2002; 9: 597–600See all References] have increased the number of low-resolution structures of these proteins from one, the Escherichia coli NhaA protein, to three. These additional structures provide the first evidence that these 12 transmembrane (TM) helix proteins have more than one arrangement of their helices and that different families of 12 TM transporters might well have evolved independently of each other to arrive at the common 12 helical structures that are seen in nature.The projection structure of the E. coli melibiose transporter, MelB, has been solved by Gerald Leblanc and colleagues at 8 A resolution [1xProjection structure at 8A resolution of the melibiose permease, an Na-sugar co-transporter from Escherichia coli. Hacksell, I. et al. EMBO J. 2002; 21: 3569–3574CrossRef | Scopus (39)See all References][1]. The 12 TM helices are arranged in an asymmetric pattern that bears some resemblance to the previously solved structure of NhaA. However, these proteins are in different families and catalyse different reactions: MelB moves melibiose into the cell along with Na+ ions (symport), whereas NhaA moves Na+ ions out of the cell while moving H+ into the cell (antiport). Higher-resolution structures are required to tell whether these are really homologous structures, but the authors have proposed that the similarity might arise because both transporters use Na+ as a ligand and that this might require a common binding domain.The second structure to be solved, most recently in 3D, is that of the Oxalobacter formigenes OxlT protein, an oxalate/formate antiporter that is a member of the MFS superfamily of transporters [2xThree-dimensional structure of a bacterial oxalate transporter. Hirai, T. et al. Nat. Struct. Biol. 2002; 9: 597–600See all References][2]. These proteins form the largest family of secondary transporters in nature and contain the most well characterized membrane transporter, the E. coli lactose permease (LacY). The structure of OxlT, solved in the labs of Sriram Subramaniam and Peter Maloney, is clearly different from both NhaA and MelB in that there is an obvious twofold symmetry in the organization of the 12 helices. The idea that the MFS proteins evolved from a duplication of a 6-TM protein to form a 12-TM protein is not new, but was previously only supported by sequence analysis and the new 3D structure confirms and extends this idea. What can be seen in the 3D structures is that as well as twofold symmetry there is fourfold symmetry in the structure and it is possible that the 6-TM predecessor was created from a duplication of an ancestral 3-TM protein.Although we still await high-resolution data for these proteins, these structures offer us glimpses of the organization of helices within each transporter. Importantly, these do not appear to all be the same and the 12 helices can be arranged in several ways. As more structures are solved it is likely that more ‘folds’ for the 12 TM helices will emerge and that we are just beginning to scratch at the surface of the diversity of structures of membrane transport proteins in nature.