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1.A.43 The Camphor Resistance or Fluoride Channel (Fluc) Family

CrcB of E. coli appears to confer camphor resistance when overexpressed and induces resA expression (Sand et al. 2003). Deletion is not lethal but increases sensitivity to camphor and fluoride. CrcB has 127 aas and 4 TMSs. Its many close homologues are small proteins, usually with 4 TMSs.  These proteins mediate fluoride resistance (Ji et al. 2014).  The active transporter is a dimer of 4 TMS subunits arranged antiparallel (Stockbridge et al. 2014).

Fluoride, F-, ubiquitous in soil, water and marine environments, is a chronic threat to microorganisms. Many bacteria, archaea, unicellular eukaryotes and plants use F- exporters to lower cytoplasmic F- levels to counteract the anion's toxicity. Stockbridge et al. 2013 and Li et al. 2013 showed that these ''Fluc'' proteins, purified and reconstituted in liposomes and planar phospholipid bilayers, form constitutively open anion channels with extreme selectivity for F- over Cl-. The active channel is a dimer of identical or homologous subunits arranged in antiparallel transmembrane orientation, or a single protein with two internal 4TMS repeats (as for the yeast proteins (TC# 1.A.43.2.4 and 5). This dual-topological assembly had not previously been seen in ion channels but is known in multidrug transporters of the SMR sub-family of the DMT superfamily (TC# 2.A.7.1) (Pornillos et al. 2005; Pornillos and Chang 2006). 

Crystal structures showed that Fluc channels contain two separate ion-conduction pathways, each with two F- binding sites (Stockbridge et al. 2015). Last et al. 2016 examined the consequences of mutating two conserved F--coordinating phenylalanine residues. Substitution of each phenylalanine specifically extinguished its associated F- binding site in crystal structures and concomitantly inhibited F- permeation. Functional analysis of concatemeric channels, which permit mutagenic manipulation of individual pores, showed that each pore can be separately inactivated without blocking F- conduction through its symmetry-related twin. The results strongly supported a dual-pathway architecture of these channels (Last et al. 2016).

References associated with 1.A.43 family:

Hu, K.H., E. Liu, K. Dean, M. Gingras, W. DeGraff, and N.J. Trun. (1996). Overproduction of three genes leads to camphor resistance and chromosome condensation in Escherichia coli. Genetics 143: 1521-1532. 8844142
Ji, C., R.B. Stockbridge, and C. Miller. (2014). Bacterial fluoride resistance, Fluc channels, and the weak acid accumulation effect. J Gen Physiol 144: 257-261. 25156118
Last, N.B., L. Kolmakova-Partensky, T. Shane, and C. Miller. (2016). Mechanistic signs of double-barreled structure in a fluoride ion channel. Elife 5:. 27449280
Li, S., K.D. Smith, J.H. Davis, P.B. Gordon, R.R. Breaker, and S.A. Strobel. (2013). Eukaryotic resistance to fluoride toxicity mediated by a widespread family of fluoride export proteins. Proc. Natl. Acad. Sci. USA 110: 19018-19023. 24173035
Pornillos, O. and G. Chang. (2006). Inverted repeat domains in membrane proteins. FEBS Lett. 580: 358-362. 16406365
Pornillos, O., Y.J. Chen, A.P. Chen, and G. Chang. (2005). X-ray structure of the EmrE multidrug transporter in complex with a substrate. Science 310: 1950-1953. 16373573
Sand, O., M. Gingras, N. Beck, C. Hall, and N. Trun. (2003). Phenotypic characterization of overexpression or deletion of the Escherichia coli crcA, cspE and crcB genes. Microbiology 149: 2107-2117. 12904550
Smith, K.D., P.B. Gordon, A. Rivetta, K.E. Allen, T. Berbasova, C. Slayman, and S.A. Strobel. (2015). Yeast Fex1p Is a Constitutively Expressed Fluoride Channel with Functional Asymmetry of Its Two Homologous Domains. J. Biol. Chem. 290: 19874-19887. 26055717
Stockbridge, R.B., A. Koide, C. Miller, and S. Koide. (2014). Proof of dual-topology architecture of Fluc F(-) channels with monobody blockers. Nat Commun 5: 5120. 25290819
Stockbridge, R.B., J.L. Robertson, L. Kolmakova-Partensky, and C. Miller. (2013). A family of fluoride-specific ion channels with dual-topology architecture. Elife 2: e01084. 23991286
Stockbridge, R.B., L. Kolmakova-Partensky, T. Shane, A. Koide, S. Koide, C. Miller, and S. Newstead. (2015). Crystal structures of a double-barrelled fluoride ion channel. Nature 525: 548-551. 26344196