Structural biology of membrane-intrinsic β-barrel enzymes: Sentinels of the bacterial outer membrane

Bishop, Russell E.

doi:10.1016/j.bbamem.2007.07.021

Cited by 113 publications

(117 citation statements)

References 188 publications

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“…Although the specifics are unclear, recent experimental studies on multiple conformations and the transient opening of membrane enzyme PagP can be interpreted as strongly suggesting the existence of unstable regions in membrane proteins (10,19,28). This dual nature of high energy on the one hand and conformational adaptability on the other may be general for the biological function of membrane proteins, which often require conformational changes (22,28,29). Although these conformational changes are initiated by exogenous perturbations, such as ligand binding, membrane depolarization, and limitation of divalent cations, the ability to adapt to such changes is already built into the protein structures in the form of weakly stable regions.…”

Section: Discussionmentioning

confidence: 99%

“…It catalyzes the palmitate transfer from a phospholipid to a glucosamine unit of a lipid in the outer leaflet and reinforces the outer leaflet to protect E. coli from a host's immune response (19)(20)(21). PagP remains dormant when the outer membrane permeability barrier is intact but can respond adaptively and instantaneously to perturbations to restore the permeability barrier (22).…”

Section: Weakly Stable Regions In the Tm Domain And Stabilization By mentioning

confidence: 99%

“…Such predictions can aid in the identification of the biological forms of ␤-barrel membrane proteins, which may require quaternary interactions between monomers. In addition, the involvement of non-barrel elements may facilitate understanding of the biological functions of ␤-barrel membrane proteins, as in the case of the out-clamp in PagP (22) and the latching loop L2 for ion selectivity in OmpF (9). Furthermore, it is envisioned that improvement in the crystallization of membrane proteins may be achieved if mutations at selected sites can be made such that these proteins are stabilized.…”

Section: Computationally Derived Energetic Models Of Membrane Proteinsmentioning

confidence: 99%

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Predicting weakly stable regions, oligomerization state, and protein–protein interfaces in transmembrane domains of outer membrane proteins

Naveed

Jackups

Liang

2009

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

110

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Although the structures of many ␤-barrel membrane proteins are available, our knowledge of the principles that govern their energetics and oligomerization states is incomplete. Here we describe a computational method to study the transmembrane (TM) domains of ␤-barrel membrane proteins. Our method is based on a physical interaction model, a simplified conformational space for efficient enumeration, and an empirical potential function from a detailed combinatorial analysis. Using this method, we can identify weakly stable regions in the TM domain, which are found to be important structural determinants for ␤-barrel membrane proteins. By calculating the melting temperatures of the TM strands, our method can also assess the stability of ␤-barrel membrane proteins. Predictions on membrane enzyme PagP are consistent with recent experimental NMR and mutant studies. We have also discovered that out-clamps, in-plugs, and oligomerization are 3 general mechanisms for stabilizing weakly stable TM regions. In addition, we have found that extended and contiguous weakly stable regions often signal the existence of an oligomer and that strands located in the interfaces of protein-protein interactions are considerably less stable. Based on these observations, we can predict oligomerization states and can identify the interfaces of protein-protein interactions for ␤-barrel membrane proteins by using either structure or sequence information. In a set of 25 nonhomologous proteins with known structures, our method successfully predicted whether a protein forms a monomer or an oligomer with 91% accuracy; in addition, our method identified with 82% accuracy the protein-protein interaction interfaces by using sequence information only when correct strands are given.in-plug ͉ membrane protein oligomerization ͉ out-clamp ͉ protein-protein interaction ͉ weakly stable TM strand D eveloping a general understanding of how proteins behave in membranes is of fundamental importance. ␤-barrel membrane proteins, one of the 2 major structural classes of membrane proteins, have been studied extensively. Currently, structures of 70 ␤-barrel membrane proteins have been resolved, and much has been learned about their thermodynamic stability (1), folding kinetics (2-4), biogenesis (5), and biological functions (6). These membrane proteins are thought to have very regular structures, with the basic principles of their architectural organization well understood (7). An overwhelming structural feature is the existence of an extensive regular hydrogen bond network between the transmembrane (TM) ␤-strands, which is thought to confer extreme stability on the proteins (8).However, ␤-barrel membrane proteins have diverse structures and often deviate significantly from the standard barrel architecture. For example, there are often small ␣-helices and ␤-strands, called in-plugs, found inside the ␤-barrel (9). Nonbarrel-embedded helices are also found to pack against the TM ␤-strands (10). In addition, some ␤-barrel membrane proteins exist in monomeric form, whe...

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Section: Discussionmentioning

confidence: 99%

Section: Weakly Stable Regions In the Tm Domain And Stabilization By mentioning

confidence: 99%

Section: Computationally Derived Energetic Models Of Membrane Proteinsmentioning

confidence: 99%

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Predicting weakly stable regions, oligomerization state, and protein–protein interfaces in transmembrane domains of outer membrane proteins

Naveed

Jackups

Liang

2009

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

110

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“…4A). This suppression was specific to PldA, because death was not suppressed by inactivating pagP (12). Knocking out PldA function is as potent a suppressor of mlaA*-mediated death as lpxC101 (Fig.…”

Section: Suppressor Analysis Implicates Increased Levels Of Lps As a mentioning

confidence: 92%

“…To prevent damage resulting from surface-exposed PLs in wild-type E. coli cells, several mechanisms destroy or remove these PLs from the outer leaflet. The OM β-barrel protein PagP is a palmitoyltransferase that removes a palmitate from the sn-1 position of a surface-exposed PL and transfers it to lipid A or phosphatidylglycerol (12,13). Another OM β-barrel phospholipase, PldA, removes both sn-1 and sn-2 palmitate moieties from PLs and lyso-PLs (14).…”

mentioning

confidence: 99%

Disruption of lipid homeostasis in the Gram-negative cell envelope activates a novel cell death pathway

Sutterlin

Shi

May

et al. 2016

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

154

197

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Gram-negative bacteria balance synthesis of the outer membrane (OM), cell wall, and cytoplasmic contents during growth via unknown mechanisms. Here, we show that a dominant mutation (designated mlaA*, maintenance of lipid asymmetry) that alters MlaA, a lipoprotein that removes phospholipids from the outer leaflet of the OM of Escherichia coli, increases OM permeability, lipopolysaccharide levels, drug sensitivity, and cell death in stationary phase. Surprisingly, single-cell imaging revealed that death occurs after protracted loss of OM material through vesiculation and blebbing at celldivision sites and compensatory shrinkage of the inner membrane, eventually resulting in rupture and slow leakage of cytoplasmic contents. The death of mlaA* cells was linked to fatty acid depletion and was not affected by membrane depolarization, suggesting that lipids flow from the inner membrane to the OM in an energy-independent manner. Suppressor analysis suggested that the dominant mlaA* mutation activates phospholipase A, resulting in increased levels of lipopolysaccharide and OM vesiculation that ultimately undermine the integrity of the cell envelope by depleting the inner membrane of phospholipids. This novel cell-death pathway suggests that balanced synthesis across both membranes is key to the mechanical integrity of the Gram-negative cell envelope.

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Bacterial Membrane Transport: Organization of Membrane Activities

Padan

2009

Encyclopedia of Life Sciences

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Bacteria have transport systems enabling them to accumulate needed nutrients, extrude unwanted by‐products and modify their cytoplasmic content of protons and salts so as to maintain a composition conducive to growth and development. Most bacterial transport systems resemble their counterparts in eukaryotic cells, and similar principles operate in both cell types. Because bacterial transporters are often easier to deal with experimentally, they have become important models for their eukaryotic brethren. The recent determination of the crystal structure of several bacterial transporters including ones that share homology with human transporters that are important in health and disease has been a major breakthrough. It opened the way both to the understanding of the mechanism of active transport as well as to rational drug design. Key concepts Cytoplasmic membrane separates the cytoplasm from the cell‐environment and at the same time communicates between these compartments by transducing signals and transporting molecules and ions across the membrane. Channels facilitate the passive transport of molecules or ions across the membrane. Transporters couple energy to actively transport molecules or ions across the membrane. Primary transport system couples transport to chemical or light energy. Secondary transport system couples transport to chemiosmotic energy. Chemiosmotic circuit couples several secondary‐ and primary transporters in a biological membrane. A virtual proton pump emerges from combining transport and metabolism. The proton motive force or the electrochemical gradient of protons across the membrane provides a reservoir of potential energy to be used in all forms of energy‐transduction across the membrane. Crystal structure of membrane proteins are critical for understanding the mechanism of transporters and for drug design for transporters involved in human's health and disease.

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Structural biology of membrane-intrinsic β-barrel enzymes: Sentinels of the bacterial outer membrane

Cited by 113 publications

References 188 publications

Predicting weakly stable regions, oligomerization state, and protein–protein interfaces in transmembrane domains of outer membrane proteins

Predicting weakly stable regions, oligomerization state, and protein–protein interfaces in transmembrane domains of outer membrane proteins

Disruption of lipid homeostasis in the Gram-negative cell envelope activates a novel cell death pathway

Bacterial Membrane Transport: Organization of Membrane Activities

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