The Clostridium perfringens TetA(P) efflux protein contains a functional variant of the Motif A region found in major facilitator superfamily transport proteins

Bannam, Trudi Leanne; Johanesen, Priscilla; Salvado, Chelsea Loree; Pidot, Sacha J.; Farrow, Kylie A; Rood, Julian I.

doi:10.1099/mic.0.26614-0

Cited by 30 publications

(17 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Point mutations of the TetA(P) efflux protein from Clostridium perfringens at the position Arg71 (equivalent to Arg77 YajR ) or Glu117 (Asp126 YajR ) are reported to disrupt its transport activity (40). Five acidic amino acids residues in the Lactococcus lactis MFS H + /drug antiporter LmrP have been shown to be essential for its transport activity (31).…”

Section: Discussionmentioning

confidence: 99%

Structure of the YajR transporter suggests a transport mechanism based on the conserved motif A

Jiang

Zhao

Wang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

167

268

View full text Add to dashboard Cite

The major facilitator superfamily (MFS) is the largest family of secondary active transporters and is present in all life kingdoms. Detailed structural basis of the substrate transport and energycoupling mechanisms of these proteins remain to be elucidated. YajR is a putative proton-driven MFS transporter found in many Gram-negative bacteria. Here we report the crystal structure of Escherichia coli YajR at 3.15 Å resolution in an outward-facing conformation. In addition to having the 12 canonical transmembrane helices, the YajR structure includes a unique 65-residue C-terminal domain which is independently stable. The structure is unique in illustrating the functional role of "sequence motif A." This highly conserved element is seen to stabilize the outward conformation of YajR and suggests a general mechanism for the conformational change between the inward and outward states of the MFS transporters.T ransporters are a type of membrane protein essential for all living cells that actively up-take nutrition and export metabolic substances and toxic materials across cellular membranes. Transporters are divided into two major types based on their energy sources. Although primary active transporters directly consume energy from ATP hydrolysis to drive substrate transport, secondary active transporters use energy derived from the electrochemical potential across the cell membrane. The major facilitator superfamily (MFS) is the largest class of secondary transporters and is present in all life kingdoms (1). For example, 25% of prokaryotic transporters belong to the MFS family (2), and the human genome contains over 110 MFS proteins (3). Currently, 3D crystal structures of nine bacterial MFS transporters (4-13) and one from fungi (9) have been reported at medium-high resolution. These studies have shown that MFS proteins contain a 12-transmembrane (TM) helix core composed of two six-helix rigid domains forming a central TM channel, which transports substrates using a rocker-switch mechanism (5). In such a mechanism, MFS proteins are believed to switch between two major conformations, inward and outward, which differ by an ∼40°rotation of one domain relative to the other. Both conformations have been captured in MFS crystal structures. However, many questions remain to be addressed, particularly those related to energy coupling and functional roles of conserved motifs.YajR, a 49-kDa transporter of the MFS family, has putatively been classified as a drug efflux protein solely on the basis of amino acid sequence analysis (14). In Escherichia coli, YajR consists of 454 amino acid residues. Besides containing 12 TM helices, YajR is predicted to possess an extra domain of about 65 residues at the C-terminal. Of the MFS proteins with reported 3D structures, the TM core of YajR shares highest sequence homology (21% identity) with EmrD (SI Appendix, Fig. S1A), which belongs to the 12-TM drug-resistance H + -driven antiporter (DHA12) subfamily (15). The YajR gene is found in a number of Gram-negative bacteria, and it shows high ...

show abstract

Section: Discussionmentioning

confidence: 99%

Structure of the YajR transporter suggests a transport mechanism based on the conserved motif A

Jiang

Zhao

Wang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

167

268

View full text Add to dashboard Cite

show abstract

“…[396] Tet efflux proteins such as Tet(P) and Tet(40) are also distributed in Clostridium . [401, 402]…”

Section: Drug Efflux In Gram-positive Bacteriamentioning

confidence: 99%

Efflux-Mediated Drug Resistance in Bacteria

Nikaido²

2009

Drugs

922

875

View full text Add to dashboard Cite

Drug efflux pumps play a key role in drug resistance and also serve other functions in bacteria. There has been a growing list of multidrug and drug-specific efflux pumps characterized from bacteria of human, animal, plant and environmental origins. These pumps are mostly encoded on the chromosome although they can also be plasmid-encoded. A previous article (Li X-Z and Nikaido H, Drugs, 2004; 64[2]: 159–204) had provided a comprehensive review regarding efflux-mediated drug resistance in bacteria. In the past five years, significant progress has been achieved in further understanding of drug resistance-related efflux transporters and this review focuses on the latest studies in this field since 2003. This has been demonstrated in multiple aspects that include but are not limited to: further molecular and biochemical characterization of the known drug efflux pumps and identification of novel drug efflux pumps; structural elucidation of the transport mechanisms of drug transporters; regulatory mechanisms of drug efflux pumps; determining the role of the drug efflux pumps in other functions such as stress responses, virulence and cell communication; and development of efflux pump inhibitors. Overall, the multifaceted implications of drug efflux transporters warrant novel strategies to combat multidrug resistance in bacteria.

show abstract

“…MFS permeases possess 12 or 14 putative or established transmembrane segments and transport many different compounds, including simple sugars, oligosaccharides, inositols, drugs, amino acids, nucleosides, organophosphate esters, Krebs cycle metabolites, and a large variety of inorganic anions and cations . Some MFS transporters may confer drug resistance on bacteria (Poelarends et al, 2002;Wigfield et al, 2002;Godreuil et al, 2003;Bannam et al, 2004). A number of plasmid-encoded MDR transporters have been described for the major human pathogen Staphylococcus aureus, including the closely related MFS members QacA and QacB (Littlejohn et al, 1992).…”

Section: Mfs Drug Transportersmentioning

confidence: 99%

Role of mycobacterial efflux transporters in drug resistance: an unresolved question

Rossi¹,

Aínsa²,

Riccardi³

2006

FEMS Microbiol Rev

262

177

View full text Add to dashboard Cite

Two mechanisms are thought to be involved in the natural drug resistance of mycobacteria: the mycobacterial cell wall permeability barrier and active multidrug efflux pumps. Genes encoding drug efflux transporters have been isolated from several mycobacterial species. These proteins transport tetracycline, fluoroquinolones, aminoglycosides and other compounds. Recent reports have suggested that efflux pumps may also be involved in transporting isoniazid, one of the main drugs used to treat tuberculosis. This review highlights recent advances in our understanding of efflux-mediated drug resistance in mycobacteria, including the distribution of efflux systems in these organisms, their substrate profiles and their contribution to drug resistance. The balance between the drug transport into the cell and drug efflux is not yet clearly understood, and further studies are required in mycobacteria.

show abstract

The Clostridium perfringens TetA(P) efflux protein contains a functional variant of the Motif A region found in major facilitator superfamily transport proteins

Cited by 30 publications

References 34 publications

Structure of the YajR transporter suggests a transport mechanism based on the conserved motif A

Structure of the YajR transporter suggests a transport mechanism based on the conserved motif A

Efflux-Mediated Drug Resistance in Bacteria

Role of mycobacterial efflux transporters in drug resistance: an unresolved question

Contact Info

Product

Resources

About