Crystal Structure of the Membrane Fusion Protein, MexA, of the Multidrug Transporter in Pseudomonas aeruginosa*

By H. Akama, T. Matsuura, S. Kashiwagi, H. Yoneyama, Shin-ichiro Narita, T. Tsukihara, A. Nakagawa, T. Nakae. 2004

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The MexAB-OprM efflux pump of Pseudomonas aeruginosa is central to multidrug resistance of this organism, which infects immunocompromised hospital patients. The MexA, MexB, and OprM subunits were assumed to function as the membrane fusion protein, the body of the transporter, and the outer membrane channel protein, respectively. For better understanding of this important xenobiotic transporter, we show the x-ray crystallographic structure of MexA at a resolution of 2.40 Å. The global MexA structure showed unforeseen new features with a spiral assembly of six and seven protomers that were joined together at one end by a pseudo 2-fold image. The protomer showed a new protein structure with a tandem arrangement consisting of at least three domains and presumably one more. The rod domain had a long hairpin of twisted coiled-coil that extended to one end. The second domain adjacent to the rod α-helical domain was globular and constructed by a cluster of eight short β-sheets. The third domain located distal to the α-helical rod was globular and composed of seven short β-sheets and one short α-helix. The 13-mer was shaped like a woven rattan cylinder with a large internal tubular space and widely opened flared ends. The 6-mer and 7-mer had a funnel-like structure consisting of a tubular rod at one side and a widely opened flared funnel top at the other side. Based on these results, we constructed a model of the MexAB-OprM pump assembly. The three pairs of MexA dimers interacted with the periplasmic α-barrel domain of OprM via the α-helical hairpin, the second domain interacted with both MexB and OprM at their contact site, and the third and disordered domains probably interacted with the distal domain of MexB. In this fashion, the MexA subunit connected MexB and OprM, indicating that MexA is the membrane bridge protein.

Subfields: Genetics, Molecular Biology, Molecular Medicine

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Citations in the corpus

Direct-coupling analysis of residue coevolution captures native contacts across many protein families (2011, background): “S7 for the protein MexA of P. aeruginosa , where 9 subunits oligomerize to form a funnel-like structure across the periplasmic space for antibiotic efflux (PDB 1vf7 (34)).”
Structure, Function, and Evolution of Bacterial ATP-Binding Cassette Systems (2008, background): “Crystal structures of the MFP MexA reveal an elongated monomer with an extended -helical coiled-coil domain and two globular domains consisting primarily of -strands (2, 199).”
Multidrug Resistance in Bacteria (2009, background): “This is because these pumps become associated with two other classes of proteins, the outer membrane channel exemplified by TolC of E. coli, belonging to the OMF (outer membrane factor) family of proteins (69) and the periplasmic “adapter” protein such as AcrA of E. coli and MexA of P. aeruginosa, c”
Efflux-Mediated Drug Resistance in Bacteria: an Update (2009, result): “The earlier crystal structures of AcrA and MexA showed elongated molecules with three linearly arranged domains: b-barrel, lipoyl and a-helical hairpin domains, but were missing the large domain containing both N- and C-terminus.([58,108,109]) However, recent reanalysis of previous MexA data resulte”
Clinically Relevant Chromosomally Encoded Multidrug Resistance Efflux Pumps in Bacteria (2006, background): “aeruginosa MexA, MexB, and OprM (3, 4, 59, 86, 133) (Fig.”