Assembling of AcrB Trimer in Cell Membrane

Lu, Wei; Chai, Qian; Zhong, Meng; Yu, Lian; Fang, Jun; Wang, Tong; Li, Huilin; Zhu, Haining; Wei, Yinan

doi:10.1016/j.jmb.2012.06.036

Cited by 18 publications

(26 citation statements)

References 41 publications

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“…Furthermore, the dissociation and/or unfolding of trimeric DAGK in lipid bicelles has been found to require weeks (Jefferson et al, 2013). High kinetic barriers to unfolding and/or dissociation of oligomers would be consistent with the slow subunit exchange observed for both DAGK and AcrB in membranes (Jefferson et al, 2013; Lu et al, 2012). Thus, in contrast to rapidly folding and unfolding single-domain soluble proteins, it is unclear whether most membrane proteins effectively achieve an equilibrium conformational ensemble in vivo .…”

Section: Energetics Of Folding and Misfolding Of α-Helical Membransupporting

confidence: 67%

The safety dance: biophysics of membrane protein folding and misfolding in a cellular context

Schlebach

Sanders

2014

Quart. Rev. Biophys.

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Most biological processes require the production and degradation of proteins, a task that weighs heavily on the cell. Mutations that compromise the conformational stability of proteins place both specific and general burdens on cellular protein homeostasis (proteostasis) in ways that contribute to numerous diseases. Efforts to elucidate the chain of molecular events responsible for diseases of protein folding address one of the foremost challenges in biomedical science. However, relatively little is known about the processes by which mutations prompt the misfolding of α-helical membrane proteins, which rely on an intricate network of cellular machinery to acquire and maintain their functional structures within cellular membranes. In this review, we summarize the current understanding of the physical principles that guide membrane protein biogenesis and folding in the context of mammalian cells. Additionally, we explore how pathogenic mutations that influence biogenesis may differ from those that disrupt folding and assembly, as well as how this may relate to disease mechanisms and therapeutic intervention. These perspectives indicate an imperative for the use of information from structural, cellular, and biochemical studies of membrane proteins in the design of novel therapeutics and in personalized medicine.

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Section: Energetics Of Folding and Misfolding Of α-Helical Membransupporting

confidence: 67%

The safety dance: biophysics of membrane protein folding and misfolding in a cellular context

Schlebach

Sanders

2014

Quart. Rev. Biophys.

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“…Indeed, AcrB is a cyclic trimer and appears to also have a slow subunit dissociation rate. 6 As kinetic stability is likely to be a favorable property for biochemical and structural studies of membrane proteins, it might therefore make sense to look for membrane protein homologs that are higher order oligomers.…”

Section: Discussionmentioning

confidence: 99%

“…Yinan Wei's lab found that upon mixing or co-expression of distinguishable subunits of the trimeric membrane protein AcrB, a non-equilibrium distribution is found. 6 This suggests that the oligomers must not exchange completely over the hours needed to express and analyze them. Subunit exchange of dimeric EmrE was also found to take many hours under native conditions.…”

Section: Introductionmentioning

confidence: 99%

Membrane Proteins Can Have High Kinetic Stability

2013

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Approximately 10% of water soluble proteins are considered kinetically stable with unfolding half-lives in the range of weeks to millenia. These proteins only rarely sample the unfolded state and may never unfold on their respective biological timescales. It is still not known whether membrane proteins can be kinetically stable, however. Here we examine the subunit dissociation rate of the trimeric membrane enzyme diacylglycerol kinase from Escherichia coli as a proxy for complete unfolding. We find that dissociation occurs with a half-life of at least several weeks, demonstrating that membrane proteins can remain locked in a folded state for long periods of time. These results reveal that evolution can use kinetic stability to regulate the biological function of membrane proteins, as it can for soluble proteins. Moreover, it appears that the generation of kinetic stability could be a viable target for membrane protein engineering efforts.

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“…AcrB purified in detergent CYMAL‐6 and DDM migrate in size exclusion chromatography with a molecular mass corresponding to trimer (Fig. 1) and appear largely trimeric when visualized by transmission electron microscopy (data not shown, [27,28]). This peak upon careful examination shows slight asymmetry that could suggest the presence of another oligomeric state.…”

Section: Discussionmentioning

confidence: 98%

A novel packing arrangement of AcrB in the lipid bilayer membrane

Bartho

Eicher

et al. 2014

FEBS Letters

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a b s t r a c tThe central component AcrB of the Escherichia coli drug efflux complex AcrA-AcrB-TolC has been extensively investigated by X-ray crystallography of detergent-protein 3-D crystals. In these crystals, AcrB packs as trimers -the functional unit. We visualized the AcrB-AcrB interaction in its native environment by examining E. coli lipid reconstituted 2-D crystals, which were overwhelmingly formed by asymmetric trimers stabilized by strongly-interacting monomers from adjacent trimers. Most interestingly, we observed lattices formed by an arrangement of AcrB monomers distinct from that in traditional trimers. This hitherto unobserved packing, might play a role in the biogenesis of trimeric AcrB.

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Assembling of AcrB Trimer in Cell Membrane

Cited by 18 publications

References 41 publications

The safety dance: biophysics of membrane protein folding and misfolding in a cellular context

The safety dance: biophysics of membrane protein folding and misfolding in a cellular context

Membrane Proteins Can Have High Kinetic Stability

A novel packing arrangement of AcrB in the lipid bilayer membrane

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