How Membranes Shape Protein Structure

White, Stephen H.; Ladokhin, Alexey S.; Jayasinghe, Sajith; Hristova, Kalina

doi:10.1074/jbc.r100008200

Cited by 294 publications

(241 citation statements)

References 68 publications

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“…The authors (Tolleter et al, 2007) observed no structural transition when the protein was exposed to lipid membranes in aqueous media; however, this is not contrary to our observations and might be expected, since the membranes were composed of neutral phospholipids, not anionic phospholipids, which for DHN1 at least are essential to membrane binding. There are indeed many examples of interactions between amphipathic a-helices and membranes that are sensitive to polarity and charges at the membrane interface and to the distribution of charged amino acid residues on helical peptides (Mishra and Palgunachari, 1996;White et al, 2001). At low water potential, columbic interaction increases due to a diminished effect of the dielectric constant of water.…”

Section: Discussionmentioning

confidence: 99%

The K-Segment of Maize DHN1 Mediates Binding to Anionic Phospholipid Vesicles and Concomitant Structural Changes

et al. 2009

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Dehydrins (DHNs; late embryogenesis abundant D11 family) are a family of intrinsically unstructured plant proteins that accumulate in the late stages of seed development and in vegetative tissues subjected to water deficit, salinity, low temperature, or abscisic acid treatment. We demonstrated previously that maize (Zea mays) DHNs bind preferentially to anionic phospholipid vesicles; this binding is accompanied by an increase in α-helicity of the protein, and adoption of α-helicity can be induced by sodium dodecyl sulfate. All DHNs contain at least one “K-segment,” a lysine-rich 15-amino acid consensus sequence. The K-segment is predicted to form a class A2 amphipathic α-helix, a structural element known to interact with membranes and proteins. Here, three K-segment deletion proteins of maize DHN1 were produced. Lipid vesicle-binding assays revealed that the K-segment is required for binding to anionic phospholipid vesicles, and adoption of α-helicity of the K-segment accounts for most of the conformational change of DHNs upon binding to anionic phospholipid vesicles or sodium dodecyl sulfate. The adoption of structure may help stabilize cellular components, including membranes, under stress conditions.

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Section: Discussionmentioning

confidence: 99%

The K-Segment of Maize DHN1 Mediates Binding to Anionic Phospholipid Vesicles and Concomitant Structural Changes

et al. 2009

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“…Because the physical forces that drive folding can change with environment, proteins in different cellular locations can be subject to distinct evolutionary constraints. Membrane proteins, in particular, must accommodate to a dramatically varied environment, ranging from hydrocarbon chains in the bilayer core to water as they emerge from the membrane (8,9). It therefore seems possible that distinct structural imperatives found in different environments could be an important contributor to evolutionary rates.…”

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confidence: 99%

Structural imperatives impose diverse evolutionary constraints on helical membrane proteins

Oberai

Joh

Pettit

et al. 2009

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

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The amino acid sequences of transmembrane regions of helical membrane proteins are highly constrained, diverging at slower rates than their extramembrane regions and than water-soluble proteins. Moreover, helical membrane proteins seem to fall into fewer families than water-soluble proteins. The reason for the differential restrictions on sequence remains unexplained. Here, we show that the evolution of transmembrane regions is slowed by a previously unrecognized structural constraint: Transmembrane regions bury more residues than extramembrane regions and soluble proteins. This fundamental feature of membrane protein structure is an important contributor to the differences in evolutionary rate and to an increased susceptibility of the transmembrane regions to disease-causing single-nucleotide polymorphisms.disease mutation ͉ potassium channel ͉ protein folding ͉ protein stability ͉ single nucleotide polymorphisms E volutionary rates vary considerably in different cellular compartments (1). Membrane proteins have been found to diverge faster overall than soluble proteins (2, 3), but this increased rate is confined entirely to the rapidly evolving extramembrane regions. Transmembrane regions, on average, diverge much more slowly than the extramembrane regions more slowly than soluble proteins (1, 4-6).A major factor controlling protein sequence divergence is the need to preserve protein function by maintaining a folded structure (7). Because the physical forces that drive folding can change with environment, proteins in different cellular locations can be subject to distinct evolutionary constraints. Membrane proteins, in particular, must accommodate to a dramatically varied environment, ranging from hydrocarbon chains in the bilayer core to water as they emerge from the membrane (8, 9). It therefore seems possible that distinct structural imperatives found in different environments could be an important contributor to evolutionary rates. An obvious sequence adaptation is the hydrophobic matching of the protein exterior, reflected in an apolar transmembrane amino acid composition. Although amino acid diversity is more limited in the transmembrane segments, simple compositional differences do not explain the slower divergence rates of transmembrane regions (1, 4, 5).Here, we find that the transmembrane regions of membrane proteins bury more residues on average than soluble proteins and much more than extramembrane regions, a possible mechanism for increasing stabilization in the absence of the hydrophobic effect. Because buried residues evolve at slower rates than surface residues (10-12), the higher level of residue burial in the transmembrane regions leads to slower sequence divergence. Moreover, we find that higher residue burial may explain a higher prevalence of disease-causing mutations in the transmembrane region of membrane proteins compared with the extramembrane regions. Results and DiscussionTransmembrane Regions Bury More Residues. Fig. 1A shows plots of the fractional surface area buried per residue v...

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“…These properties are also expected to modulate the thermodynamic stability of membrane proteins because the membrane environment imposes very different mechanical constraints (6, 7) on membrane proteins than water does on soluble proteins (8). A thorough understanding of the factors that determine the stability of membrane proteins is of fundamental theoretical interest to understand the forces that shape these proteins (9). Accurate assessments of their thermodynamic stability will also aid in the design of more stable membrane proteins for therapeutic applications and for structural studies of this structurally underrepresented class of proteins.…”

mentioning

confidence: 99%

Elastic coupling of integral membrane protein stability to lipid bilayer forces

Hong

Tamm

2004

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

217

247

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It has been traditionally difficult to measure the thermodynamic stability of membrane proteins because fully reversible protocols for complete folding these proteins were not available. Knowledge of the thermodynamic stability of membrane proteins is desirable not only from a fundamental theoretical standpoint, but is also of enormous practical interest for the rational design of membrane proteins and for optimizing conditions for their structure determination by crystallography or NMR. Here, we describe the design of a fully reversible system to study equilibrium folding of the outer membrane protein A from Escherichia coli in lipid bilayers. Folding is shown to be two-state under appropriate conditions permitting data analysis with a classical folding model developed for soluble proteins. The resulting free energy and m value, i.e., a measure of cooperativity, of unfolding are ⌬G T he material elastic properties of biological membranes such as curvature stress and bilayer deformation from hydrophobic mismatch have emerged as important functional modulators of ion channels, receptors, and other integral membrane proteins (1-5). These properties are also expected to modulate the thermodynamic stability of membrane proteins because the membrane environment imposes very different mechanical constraints (6, 7) on membrane proteins than water does on soluble proteins (8). A thorough understanding of the factors that determine the stability of membrane proteins is of fundamental theoretical interest to understand the forces that shape these proteins (9). Accurate assessments of their thermodynamic stability will also aid in the design of more stable membrane proteins for therapeutic applications and for structural studies of this structurally underrepresented class of proteins. For example, overcoming conformational dynamics has been a major breakthrough in the recent determination of the structure of lactose permease (10) and superstable mutants of diacylglycerolkinase have dramatically improved crystallization and NMR conditions (11,12). Unfortunately, quantitative studies of membrane protein stability have been hampered by difficulties to completely and reversibly unfold these proteins (13,14). We have now designed a fully reversible system to study equilibrium folding of membrane proteins in lipid bilayers, by using the outer membrane protein A (OmpA) from Escherichia coli as a model. OmpA is an abundant protein of the outer membranes of Gram-negative bacteria, where it serves a structural role and also functions as a phage and colicin receptor. The eight-stranded ␤-barrel structure of the N-terminal transmembrane domain (residues 1-177) has been solved by x-ray crystallography (15) and NMR (16). Denatured OmpA in solution spontaneously refolds into lipid bilayer membranes after dilution of denaturants (17), and the kinetics of refolding of OmpA have been shown to depend on the composition, thickness, and overall curvature of the lipid bilayer (18). We demonstrate here that OmpA folding into lipid bilayers is a ...

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How Membranes Shape Protein Structure

Cited by 294 publications

References 68 publications

The K-Segment of Maize DHN1 Mediates Binding to Anionic Phospholipid Vesicles and Concomitant Structural Changes

The K-Segment of Maize DHN1 Mediates Binding to Anionic Phospholipid Vesicles and Concomitant Structural Changes

Structural imperatives impose diverse evolutionary constraints on helical membrane proteins

Elastic coupling of integral membrane protein stability to lipid bilayer forces

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