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AcrA is a Multidrug efflux system protein. It belongs to resistance nodulation cell division (RND) family protein, which utilize electrochemical gradient to energize efflux of antibiotics and other compounds out of the bacterial cells (Putman et al 2000). RND system consists of large complexes of three essential proteins and work together as a multiprotein efflux system. Two most studied RND systems are E. coli AcrA-AcrB-TolC and P. aeruginosa MexA-MexB-OprM, which are known to efflux antibiotics, heavy metals, dyes, detergents, solvents, plus many other substrates (Ayush Kumar, Herbert P. Schweizer 2005).

Stable core of AcrA

Four molecules of AcrA (45-312 residues) in asymmetric unit of the crystal pack as an apparent . Each monomers are labeled as A (in cyan), B (in orange), C (in green) and D (in yellow). A, B / C, D are related to one another by approximate . Each set of dimers are related to one another by approximate 2 fold axis (Jonathan Mikolosko, Kostyantyn Bobyk, Helen I. Zgurskaya, and Partho Ghosh, 2006). Each monomer is a sickle shaped molecule comprising three domains viz. β-barrel domain, lipoyl domain, and coiled coil α-helical hairpin domain. β-barrel domain comprises six anti-parallel β-sheets and a short α-helix. Lipoyl domain is present in the central part of the AcrA monomer made up of two half motifs interrupted by an α-helical hairpin. Each half of the lipoyl motif is homologous to each other and consist of four β-strands in the form of a β-sandwich. A conserved lysine residue on the connecting loop of two half motifs serve as carrier of lipoyl or biotinyl co-factors. The coiled coil domain consists of five heptad repeats per helix. Two α-helices are packed together as a canonical knobs-into-holes by hydrophobic side chains in the a and d positions of the heptad repeats (Johnson and Church 1999, Akama et al 2004). Crystal structure provide evidence for the flexibility of the hinge region between α-helical hairpin and lipoyl domain. The difference in hinge angle in case of B and C chain varies approximately by 15o overall and 21 Å at the loop located at the top of the hairpin.

Assembly within biological system

AcrA is present within E. coli cells as a part of tripartite membrane associated efflux system along with AcrB and TolC. AcrA is present in the periplasmic space of cell with the proton antiporter AcrB in the inner-membrane and channel TolC in the outer membrane. It can it can remain free or form bipartite complexes with AcrB and TolC. The lipoyl and β-barrel domain of AcrA interact with AcrB, whereas the α-helical hairpin domain interact with TolC (Qiang Ge et al, 2009). ArcA remains attached to the inner membrane via lipid acylation of Cys-25. N and C termini of AcrA form two β-stand, β1 (54-61) and β14 (292-297). A 28 flexible residues connects acylated Cys-25 with the β-barrel domain and allow the protein to reach the periplasmic top of AcrB (Yu et al 2003). A short α-helix (222-230) located between β-10 and β-11 closes off the end of the β-barrel near the C-terminus of AcrA fragment. Approximately 100 residues in the C-terminal are predicted to be important for AcrAB-TolC interaction.