ID   ALX_ECOLI               Reviewed;         321 AA.
AC   P42601; Q2M9B8; Q6BF48;
DT   01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT   11-OCT-2004, sequence version 2.
DT   02-SEP-2026, entry version 146.
DE   RecName: Full=Manganese exporter Alx {ECO:0000305};
GN   Name=alx {ECO:0000303|PubMed:2108134}; Synonyms=ygjT;
GN   OrderedLocusNames=b3088, JW5515;
OS   Escherichia coli (strain K12).
OC   Bacteria; Pseudomonadati; Pseudomonadota; Gammaproteobacteria;
OC   Enterobacterales; Enterobacteriaceae; Escherichia.
OX   NCBI_TaxID=83333;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=K12 / MG1655 / ATCC 47076;
RX   PubMed=9278503; DOI=10.1126/science.277.5331.1453;
RA   Blattner F.R., Plunkett G. III, Bloch C.A., Perna N.T., Burland V.,
RA   Riley M., Collado-Vides J., Glasner J.D., Rode C.K., Mayhew G.F.,
RA   Gregor J., Davis N.W., Kirkpatrick H.A., Goeden M.A., Rose D.J., Mau B.,
RA   Shao Y.;
RT   "The complete genome sequence of Escherichia coli K-12.";
RL   Science 277:1453-1462(1997).
RN   [2]
RP   SEQUENCE REVISION TO 172-179.
RX   PubMed=16397293; DOI=10.1093/nar/gkj405;
RA   Riley M., Abe T., Arnaud M.B., Berlyn M.K.B., Blattner F.R.,
RA   Chaudhuri R.R., Glasner J.D., Horiuchi T., Keseler I.M., Kosuge T.,
RA   Mori H., Perna N.T., Plunkett G. III, Rudd K.E., Serres M.H., Thomas G.H.,
RA   Thomson N.R., Wishart D., Wanner B.L.;
RT   "Escherichia coli K-12: a cooperatively developed annotation snapshot
RT   -- 2005.";
RL   Nucleic Acids Res. 34:1-9(2006).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=K12 / W3110 / ATCC 27325 / DSM 5911;
RX   PubMed=16738553; DOI=10.1038/msb4100049;
RA   Hayashi K., Morooka N., Yamamoto Y., Fujita K., Isono K., Choi S.,
RA   Ohtsubo E., Baba T., Wanner B.L., Mori H., Horiuchi T.;
RT   "Highly accurate genome sequences of Escherichia coli K-12 strains MG1655
RT   and W3110.";
RL   Mol. Syst. Biol. 2:E1-E5(2006).
RN   [4]
RP   GENE NAME, AND INDUCTION.
RC   STRAIN=K12;
RX   PubMed=2108134; DOI=10.1128/jb.172.4.2184-2186.1990;
RA   Bingham R.J., Hall K.S., Slonczewski J.L.;
RT   "Alkaline induction of a novel gene locus, alx, in Escherichia coli.";
RL   J. Bacteriol. 172:2184-2186(1990).
RN   [5]
RP   INDUCTION.
RC   STRAIN=K12;
RX   PubMed=12107143; DOI=10.1128/jb.184.15.4246-4258.2002;
RA   Stancik L.M., Stancik D.M., Schmidt B., Barnhart D.M., Yoncheva Y.N.,
RA   Slonczewski J.L.;
RT   "pH-dependent expression of periplasmic proteins and amino acid catabolism
RT   in Escherichia coli.";
RL   J. Bacteriol. 184:4246-4258(2002).
RN   [6]
RP   SUBCELLULAR LOCATION, AND TOPOLOGY [LARGE SCALE ANALYSIS].
RC   STRAIN=K12 / MG1655 / ATCC 47076;
RX   PubMed=15919996; DOI=10.1126/science.1109730;
RA   Daley D.O., Rapp M., Granseth E., Melen K., Drew D., von Heijne G.;
RT   "Global topology analysis of the Escherichia coli inner membrane
RT   proteome.";
RL   Science 308:1321-1323(2005).
RN   [7]
RP   REGULATION OF EXPRESSION.
RX   PubMed=19933154; DOI=10.1101/gad.552209;
RA   Nechooshtan G., Elgrably-Weiss M., Sheaffer A., Westhof E., Altuvia S.;
RT   "A pH-responsive riboregulator.";
RL   Genes Dev. 23:2650-2662(2009).
RN   [8]
RP   REGULATION OF EXPRESSION.
RX   PubMed=24078087; DOI=10.1093/nar/gkt868;
RA   Nechooshtan G., Elgrably-Weiss M., Altuvia S.;
RT   "Changes in transcriptional pausing modify the folding dynamics of the pH-
RT   responsive RNA element.";
RL   Nucleic Acids Res. 42:622-630(2014).
RN   [9]
RP   REGULATION OF EXPRESSION.
RC   STRAIN=K12 / MG1655 / ATCC 47076;
RX   PubMed=25794618; DOI=10.1016/j.molcel.2015.01.035;
RA   Dambach M., Sandoval M., Updegrove T.B., Anantharaman V., Aravind L.,
RA   Waters L.S., Storz G.;
RT   "The ubiquitous yybP-ykoY riboswitch is a manganese-responsive regulatory
RT   element.";
RL   Mol. Cell 57:1099-1109(2015).
RN   [10]
RP   FUNCTION, AND DISRUPTION PHENOTYPE.
RX   PubMed=29440394; DOI=10.1074/jbc.m117.790717;
RA   Zeinert R., Martinez E., Schmitz J., Senn K., Usman B., Anantharaman V.,
RA   Aravind L., Waters L.S.;
RT   "Structure-function analysis of manganese exporter proteins across
RT   bacteria.";
RL   J. Biol. Chem. 293:5715-5730(2018).
RN   [11]
RP   REGULATION OF EXPRESSION.
RX   PubMed=35934054; DOI=10.1016/j.jbc.2022.102302;
RA   Stephen C., Mishanina T.V.;
RT   "Alkaline pH has an unexpected effect on transcriptional pausing during
RT   synthesis of the Escherichia coli pH-responsive riboswitch.";
RL   J. Biol. Chem. 298:102302-102302(2022).
RN   [12]
RP   FUNCTION, ACTIVITY REGULATION, REGULATION OF EXPRESSION, AND MUTAGENESIS OF
RP   ASP-24; ASP-73; GLU-86; ASP-92; GLU-213; ASP-216; ASP-222 AND ASP-284.
RC   STRAIN=K12 / MC4100 / ATCC 35695 / DSM 6574;
RX   PubMed=38869303; DOI=10.1128/jb.00168-24;
RA   Sharma R., Mishanina T.V.;
RT   "A riboswitch-controlled TerC family transporter Alx tunes intracellular
RT   manganese concentration in Escherichia coli at alkaline pH.";
RL   J. Bacteriol. 206:e0016824-e0016824(2024).
CC   -!- FUNCTION: Functions as a low-activity manganese exporter at alkaline pH
CC       (PubMed:38869303). Involved in manganese homeostasis (PubMed:29440394,
CC       PubMed:38869303). Alx-mediated manganese export serves as a primary
CC       protective mechanism that fine tunes the cytoplasmic manganese content,
CC       especially during alkaline stress (PubMed:38869303). Transport of
CC       Mn(2+) by Alx is unlikely to be accompanied by an H(+) antiport
CC       (PubMed:38869303). Alx does not participate in maintaining cellular pH
CC       (PubMed:38869303). {ECO:0000269|PubMed:29440394,
CC       ECO:0000269|PubMed:38869303}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=Mn(2+)(in) = Mn(2+)(out); Xref=Rhea:RHEA:28699,
CC         ChEBI:CHEBI:29035; Evidence={ECO:0000305|PubMed:38869303};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:28700;
CC         Evidence={ECO:0000305|PubMed:38869303};
CC   -!- ACTIVITY REGULATION: The export activity is maximal at alkaline pH.
CC       {ECO:0000269|PubMed:38869303}.
CC   -!- SUBCELLULAR LOCATION: Cell inner membrane
CC       {ECO:0000269|PubMed:15919996}; Multi-pass membrane protein
CC       {ECO:0000255}.
CC   -!- INDUCTION: Induced by extreme alkaline conditions (PubMed:12107143,
CC       PubMed:19933154, PubMed:2108134, PubMed:35934054, PubMed:38869303).
CC       Expression is also up-regulated by elevated concentrations of Mn(2+)
CC       (PubMed:25794618, PubMed:38869303). The effects of alkaline pH and
CC       elevated extracellular Mn(2+) concentrations on alx expression are
CC       additive (PubMed:38869303). The alkalinization of media increases the
CC       cytoplasmic manganese pool, which, in turn, enhances alx expression
CC       (PubMed:38869303). The regulation of expression is achieved via a pH-
CC       responsive RNA element (PRE) riboswitch, located in the 5' untranslated
CC       region (5'-UTR) of alx, which regulates both transcription and
CC       translation of alx in response to environmental pH (PubMed:19933154,
CC       PubMed:38869303). The 5'-UTR can form alternative secondary structures
CC       depending on the pH (PubMed:19933154). Under normal growth conditions
CC       this RNA region forms a translationally inactive structure, but when
CC       exposed to high pH, a translationally active structure is formed
CC       (PubMed:19933154). In this active structure, the ribosome-binding site
CC       is exposed, leading to translation of Alx (PubMed:19933154). The
CC       riboswitch is also responsive to Mn(2+) (PubMed:25794618,
CC       PubMed:38869303). The riboswitch directly binds Mn(2+), resulting in a
CC       conformation that liberates the ribosome-binding site, leading to
CC       increased translation (PubMed:25794618). The folding of PRE into a
CC       translationally active structure to produce Alx is modulated by RNA
CC       polymerase (RNAP) pausing (PubMed:19933154, PubMed:24078087). However,
CC       modulation of RNAP pausing alone seems insufficient to explain the
CC       alternative PRE folding outcomes under different pH, and RNA itself may
CC       actively participate in the sensing of pH (PubMed:35934054).
CC       {ECO:0000269|PubMed:12107143, ECO:0000269|PubMed:19933154,
CC       ECO:0000269|PubMed:2108134, ECO:0000269|PubMed:24078087,
CC       ECO:0000269|PubMed:25794618, ECO:0000269|PubMed:35934054,
CC       ECO:0000269|PubMed:38869303}.
CC   -!- DISRUPTION PHENOTYPE: The deletion mutant does not display a
CC       sensitivity to high manganese concentration, high pH, or both high
CC       manganese concentration and high pH together.
CC       {ECO:0000269|PubMed:29440394}.
CC   -!- MISCELLANEOUS: Overexpression can rescue the growth of the mntP
CC       deletion mutant in alkaline media with added Mn(2+).
CC       {ECO:0000269|PubMed:38869303}.
CC   -!- SIMILARITY: Belongs to the TerC family. {ECO:0000305}.
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DR   EMBL; U18997; AAA57890.1; -; Genomic_DNA.
DR   EMBL; U00096; AAT48166.1; -; Genomic_DNA.
DR   EMBL; AP009048; BAE77138.1; -; Genomic_DNA.
DR   PIR; E65097; E65097.
DR   RefSeq; WP_001098806.1; NZ_CP009789.1.
DR   RefSeq; YP_026201.1; NC_000913.3.
DR   AlphaFoldDB; P42601; -.
DR   BioGRID; 4262405; 14.
DR   FunCoup; P42601; 342.
DR   STRING; 511145.b3088; -.
DR   TCDB; 2.A.109.1.7; the tellurium ion resistance (terc) family.
DR   PaxDb; 511145-b3088; -.
DR   EnsemblBacteria; AAT48166; AAT48166; b3088.
DR   GeneID; 947607; -.
DR   KEGG; ecj:JW5515; -.
DR   KEGG; eco:b3088; -.
DR   KEGG; ecoc:C3026_16865; -.
DR   PATRIC; fig|1411691.4.peg.3641; -.
DR   EchoBASE; EB2589; -.
DR   eggNOG; COG0861; Bacteria.
DR   HOGENOM; CLU_045644_1_2_6; -.
DR   InParanoid; P42601; -.
DR   OMA; ADHAREY; -.
DR   OrthoDB; 9783692at2; -.
DR   PhylomeDB; P42601; -.
DR   BioCyc; EcoCyc:G7607-MONOMER; -.
DR   PRO; PR:P42601; -.
DR   Proteomes; UP000000625; Chromosome.
DR   GO; GO:0005886; C:plasma membrane; IDA:EcoCyc.
DR   GO; GO:0071467; P:cellular response to pH; IDA:EcoCyc.
DR   InterPro; IPR005496; Integral_membrane_TerC.
DR   InterPro; IPR022369; Integral_membrane_TerC_rswitch.
DR   NCBIfam; TIGR03718; R_switched_Alx; 1.
DR   PANTHER; PTHR30238; MEMBRANE BOUND PREDICTED REDOX MODULATOR; 1.
DR   PANTHER; PTHR30238:SF0; THYLAKOID MEMBRANE PROTEIN TERC, CHLOROPLASTIC; 1.
DR   Pfam; PF03741; TerC; 1.
PE   1: Evidence at protein level;
KW   Cell inner membrane; Cell membrane; Ion transport; Manganese; Membrane;
KW   Reference proteome; Transmembrane; Transmembrane helix; Transport.
FT   CHAIN           1..321
FT                   /note="Manganese exporter Alx"
FT                   /id="PRO_0000103410"
FT   TOPO_DOM        1..6
FT                   /note="Periplasmic"
FT                   /evidence="ECO:0000305"
FT   TRANSMEM        7..27
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        28..43
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000305"
FT   TRANSMEM        44..64
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        65..89
FT                   /note="Periplasmic"
FT                   /evidence="ECO:0000305"
FT   TRANSMEM        90..110
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        111..113
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000305"
FT   TRANSMEM        114..134
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        135
FT                   /note="Periplasmic"
FT                   /evidence="ECO:0000305"
FT   TRANSMEM        136..156
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        157..198
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000305"
FT   TRANSMEM        199..219
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        220..225
FT                   /note="Periplasmic"
FT                   /evidence="ECO:0000305"
FT   TRANSMEM        226..246
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        247..261
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000305"
FT   TRANSMEM        262..282
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        283..286
FT                   /note="Periplasmic"
FT                   /evidence="ECO:0000305"
FT   TRANSMEM        287..307
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        308..321
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000269|PubMed:15919996"
FT   MUTAGEN         24
FT                   /note="D->N: Does not affect activity, can complement a
FT                   mntP deletion mutant."
FT                   /evidence="ECO:0000269|PubMed:38869303"
FT   MUTAGEN         73
FT                   /note="D->N: Does not affect activity, can complement a
FT                   mntP deletion mutant."
FT                   /evidence="ECO:0000269|PubMed:38869303"
FT   MUTAGEN         86
FT                   /note="E->Q: Loss of activity, cannot complement a mntP
FT                   deletion mutant."
FT                   /evidence="ECO:0000269|PubMed:38869303"
FT   MUTAGEN         92
FT                   /note="D->N: Loss of activity, cannot complement a mntP
FT                   deletion mutant."
FT                   /evidence="ECO:0000269|PubMed:38869303"
FT   MUTAGEN         213
FT                   /note="E->Q: Loss of activity, cannot complement a mntP
FT                   deletion mutant."
FT                   /evidence="ECO:0000269|PubMed:38869303"
FT   MUTAGEN         216
FT                   /note="D->N: Loss of activity, cannot complement a mntP
FT                   deletion mutant."
FT                   /evidence="ECO:0000269|PubMed:38869303"
FT   MUTAGEN         222
FT                   /note="D->N: Loss of activity, cannot complement a mntP
FT                   deletion mutant."
FT                   /evidence="ECO:0000269|PubMed:38869303"
FT   MUTAGEN         284
FT                   /note="D->N: Does not affect activity, can complement a
FT                   mntP deletion mutant."
FT                   /evidence="ECO:0000269|PubMed:38869303"
FT   CONFLICT        172..179
FT                   /note="PLVRWLRG -> RWCAGYAV (in Ref. 1; AAA57890)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   321 AA;  35909 MW;  B6E1C173442799C3 CRC64;
     MNTVGTPLLW GGFAVVVAIM LAIDLLLQGR RGAHAMTMKQ AAAWSLVWVT LSLLFNAAFW
     WYLVQTEGRA VADPQALAFL TGYLIEKSLA VDNVFVWLML FSYFSVPAAL QRRVLVYGVL
     GAIVLRTIMI FTGSWLISQF DWILYIFGAF LLFTGVKMAL AHEDESGIGD KPLVRWLRGH
     LRMTDTIDNE HFFVRKNGLL YATPLMLVLI LVELSDVIFA VDSIPAIFAV TTDPFIVLTS
     NLFAILGLRA MYFLLAGVAE RFSMLKYGLA VILVFIGIKM LIVDFYHIPI AVSLGVVFGI
     LVMTFIINAW VNYRHDKQRG G
//