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Function, Structure, and Evolution of the Major Facilitator Superfamily: The LacY Manifesto

DOI: 10.1155/2014/523591

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Abstract:

The major facilitator superfamily (MFS) is a diverse group of secondary transporters with members found in all kingdoms of life. A paradigm for MFS is the lactose permease (LacY) of Escherichia coli, which couples the stoichiometric translocation of a galactopyranoside and an across the cytoplasmic membrane. LacY has been the test bed for the development of many methods applied for the analysis of transport proteins. X-ray structures of an inward-facing conformation and the most recent structure of an almost occluded conformation confirm many conclusions from previous studies. Although structure models are critical, they are insufficient to explain the catalysis of transport. The clues to understanding transport are based on the principles of enzyme kinetics. Secondary transport is a dynamic process—static snapshots of X-ray crystallography describe it only partially. However, without structural information, the underlying chemistry is virtually impossible to conclude. A large body of biochemical/biophysical data derived from systematic studies of site-directed mutants in LacY suggests residues critically involved in the catalysis, and a working model for the symport mechanism that involves alternating access of the binding site is presented. The general concepts derived from the bacterial LacY are examined for their relevance to other MFS transporters. 1. Introduction Proteins can act as molecular devices to convert one energy form to another through cycles of conformational transitions. Symporters, antiporters, transporters, carriers, or permeases are such molecular devices that catalyze substrate-specific equilibration and/or translocation of solutes across a biological membrane (Figure 1(a)). In 1955, when the existence of cell membranes themselves was still being questioned, let alone the existence of proteins that transport solutes specifically across them, Cohen and Rickenberg [1] found an inducible transport system for lactose in Escherichia coli, and it was subsequently found to be part of the famous lac operon [2]. This discovery was the first time that a transport function was associated with genetics and indicated that a protein might be involved. Figure 1: Transport reactions catalyzed by MFS. (a) Schematic illustration of active transports (symport, e.g., LacY, and antiport, e.g., GlpT) and facilitated diffusion (e.g., GLUT1). The red and green arrows indicate the transport directions of substrate and cosubstrate. (b) Uphill substrate (S) accumulation in response to generated by either respiration or ATP hydrolysis by F 1F O-ATPase. (c)

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