2.A.1.5.1
β- and α-galactopyranoside:H⁺ symporter, LacY. Transports lactose, melibiose, thio-β-methyl galactopyranoside (TMG), isopropyl-β-thiogalactoside (IPTG), 4-nitrophenyl-beta-D-galactopyranoside, 4-nitrophenyl-alpha-D-galactopyranoside and galactopyranosyl-1-glycerol. Single point mutations allow transport of sucrose and maltose (King and Wilson 1990).  Crystal structures and modeling reveal the cytoplasmic open state and the periplasmic open state (PDB ID: 1PV7). A structure with a bound lactose homolog, beta-D-galactopyranosyl-1-thio-beta-D-galactopyranoside, revealed the sugar-binding site in a cavity, and residues that play major roles in substrate recognition and proton translocation were identified (Abramson et al., 2003; Pendse et al., 2010). The membrane lipid composition determines the topology of LacY (Dowhan and Bogdanov, 2011). Smirnova et al. (2011) have provided evidence that the opening of the periplasmic cavity in LacY is the limiting step for sugar binding. Evidence for an alternating sites mechanism of transport has been summarized (Smirnova et al., 2011). Eames and Kortemme (2012) have shown that when considering expression of the lac operon, LacY function (H⁺ co-transport) and not protein production is the primary origin of cost fitness. Homology threading of several MFS porters based on the LacY 3-d structure has been reported (Kasho et al., 2006). The alternating-access mechanism has been suggested to arise from inverted topological repeats (Radestock and Forrest, 2011; Madej et al. 2012), but this proposal has been contested (Västermark and Saier 2014; Västermark et al. 2014). Mechanistic features of LacY have been summarized (Kaback 2015). Insertion into the membrane depends on YidC (TC# 2.A.9.3.1) and may occur in a stepwise, stochastic manner employing multiple coexisting pathways to complete the folding process (Serdiuk et al. 2017). The glucose Enzyme IIA (Crr) protein binds LacY to allosterically inhibit its activity, promoting inducer exclusion (Hoischen et al. 1996; Hariharan et al. 2015). Protonated LacY binds D-galactopyranosides specifically, inducing an occluded state that can open to either side of the membrane (Kumar et al. 2014). LacY can form amyloid-like fibrils under destabilizing conditions (Stroobants et al. 2017). Multiple conformations of LacY have been solved (Kumar et al. 2018).  Direct interactions between LacY and its lipid environment uniquely contribute to its membrane protein organization and function (Vitrac et al. 2020). The lactose permease purified from E. coli exhibiting varied phospholipid compositions has the same topology and function as in its membrane of origin (Vitrac et al. 2019).