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2.A.7.1.3
Small cationic multidrug efflux pump (substrates: cationic lipophilic drugs), EmrE. This pump confers resistance to a wide range of disinfectants and dyes known as quaternary cation compounds (QCCs). The 3-D structure of the dimeric EmrE shows opposite orientation of the two subunits in the membrane (Chen et al., 2007), and this conclusion has been confirmed (Fleishman et al. 2006; Lehner et al. 2008; Lloris-Garcerá et al. 2013). There may be a single intermediate state in which the substrate is occluded and immobile (Basting et al., 2008).  Direct interaction between substrates (tetraphenylphosphonium, TPP+ and MTP+) and Glu14 in TMS1 has been demonstrated using solid state NMR (Ong et al. 2013). A Gly90X6Gly97 motif is important for dimer formation (Elbaz et al., 2008).  Two models may account for the opposite (inverted) orientations of the two identical subunits. A post-translational model posits that topology remains malleable after synthesis and becomes fixed once the dimer forms. A second, co-translational model, posits that the protein inserts in both topologies in equal proportions (Woodall et al. 2015).  Protonation of E14 leads to rotation and tilt of transmembrane helices 1-3 in conjunction with repacking of loops, conformational changes that alter the coordination of the bound substrate and modulate its access to the binding site from the lipid bilayer. The transport model that emerges posits a proton-bound, but occluded, resting state. Substrate binding from the inner leaflet of the bilayer releases the protons and triggers alternating access between inward- and outward-facing conformations of the substrate-loaded transporter, thus enabling antiport without dissipation of the proton gradient (Dastvan et al. 2016). TMS4 is the known dimerization domain of EmrE (Julius et al. 2017). Few conserved residues are essential for drug polyselectivity. Aromatic QCC selection involves a greater portion of conserved residues compared to other QCCs (Saleh et al. 2018).
     The topologies of helical membrane proteins are generally defined during insertion of the transmembrane helices, yet topology can change after insertion. In EmrE, topology flipping occurs so that the populations in both orientations equalize. Woodall et al. 2017 demonstrated that when EmrE is forced to insert in a distorted topology, topology flipping of the first TMS can occur, and topological malleability also extends to the C-terminal helix; even complete inversion of the entire EmrE protein can occur after the full protein is translated and inserted. Thus, topological rearrangements appear to be possible during biogenesis. Subtle but significant differences in the sizes of EmrE with different QCC ligands bound has been reported (Qazi and Turner 2018).

Accession Number:P23895
Protein Name:EmrE aka MVRC aka EB aka B0543
Length:110
Molecular Weight:11958.00
Species:Escherichia coli [83333]
Number of TMSs:4
Location1 / Topology2 / Orientation3: Cell inner membrane1 / Multi-pass membrane protein2
Substrate cationic dyes, tetraphenylphosphonium, TPP, ethidium, quaternary cationic compounds, Cationic lipophilic drugs

Cross database links:

Genevestigator: P23895
EchoBASE: EB0623
EcoGene: EG10629
eggNOG: COG2076
HEGENOM: HBG740972
DIP: DIP-9505N
RefSeq: AP_001188.1    NP_415075.1   
Entrez Gene ID: 948442   
Pfam: PF00893   
BioCyc: EcoCyc:EMRE-MONOMER    ECOL168927:B0543-MONOMER   
KEGG: ecj:JW0531    eco:b0543   

Gene Ontology

GO:0016021 C:integral to membrane
GO:0005886 C:plasma membrane
GO:0015297 F:antiporter activity
GO:0042493 P:response to drug
GO:0006810 P:transport
GO:0006805 P:xenobiotic metabolic process

References (24)

[1] “Nucleotide sequence of the ethidium efflux gene from Escherichia coli.”  Purewal A.S.et.al.   1936950
[2] “Cloning and characterization of the mvrC gene of Escherichia coli K-12 which confers resistance against methyl viologen toxicity.”  Morimyo M.et.al.   1320256
[3] “The complete genome sequence of Escherichia coli K-12.”  Blattner F.R.et.al.   9278503
[4] “Highly accurate genome sequences of Escherichia coli K-12 strains MG1655 and W3110.”  Hayashi K.et.al.   16738553
[5] “EmrE, an Escherichia coli 12-kDa multidrug transporter, exchanges toxic cations and H+ and is soluble in organic solvents.”  Yerushalmi H.et.al.   7896833
[6] “EmrE, the smallest ion-coupled transporter, provides a unique paradigm for structure-function studies.”  Schuldiner S.et.al.   9050242
[7] “An essential glutamyl residue in EmrE, a multidrug antiporter from Escherichia coli.”  Yerushalmi H.et.al.   10681497
[8] “Small is mighty: EmrE, a multidrug transporter as an experimental paradigm.”  Schuldiner S.et.al.   11443233
[9] “An amino acid cluster around the essential Glu-14 is part of the substrate- and proton-binding domain of EmrE, a multidrug transporter from Escherichia coli.”  Gutman N.et.al.   12590142
[10] “The membrane topology of EmrE - a small multidrug transporter from Escherichia coli.”  Ninio S.et.al.   15044024
[11] “New insights into the structure and oligomeric state of the bacterial multidrug transporter EmrE: an unusual asymmetric homo-dimer.”  Ubarretxena-Belandia I.et.al.   15111102
[12] “EmrE, a multidrug transporter from Escherichia coli, transports monovalent and divalent substrates with the same stoichiometry.”  Rotem D.et.al.   15371426
[13] “In vitro synthesis of fully functional EmrE, a multidrug transporter, and study of its oligomeric state.”  Elbaz Y.et.al.   14755055
[14] “Substrate-induced tryptophan fluorescence changes in EmrE, the smallest ion-coupled multidrug transporter.”  Elbaz Y.et.al.   15882076
[15] “Exploring the binding domain of EmrE, the smallest multidrug transporter.”  Sharoni M.et.al.   16049002
[16] “Global topology analysis of the Escherichia coli inner membrane proteome.”  Daley D.O.et.al.   15919996
[17] “Identification of tyrosine residues critical for the function of an ion-coupled multidrug transporter.”  Rotem D.et.al.   16672221
[18] “On parallel and antiparallel topology of a homodimeric multidrug transporter.”  Soskine M.et.al.   17003034
[19] “NMR investigation of the multidrug transporter EmrE, an integral membrane protein.”  Schwaiger M.et.al.   9688273
[20] “Three-dimensional structure of the bacterial multidrug transporter EmrE shows it is an asymmetric homodimer.”  Ubarretxena-Belandia I.et.al.   14633977
[21] “Structure of the multidrug resistance efflux transporter EmrE from Escherichia coli.”  Ma C.et.al.   14970332
[22] “X-ray structure of the EmrE multidrug transporter in complex with a substrate.”  Pornillos O.et.al.   16373573
[23] “”  Chang G.et.al.   17185584
[24] “Quasi-symmetry in the cryo-EM structure of EmrE provides the key to modeling its transmembrane domain.”  Fleishman S.J.et.al.   17005200
Structure:
2I68   3B5D   3B61   3B62     

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FASTA formatted sequence
1:	MNPYIYLGGA ILAEVIGTTL MKFSEGFTRL WPSVGTIICY CASFWLLAQT LAYIPTGIAY 
61:	AIWSGVGIVL ISLLSWGFFG QRLDLPAIIG MMLICAGVLI INLLSRSTPH