Transmembrane glycine zippers: physiological and pathological roles in membrane proteins (original) (raw)
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Proceedings of the National Academy of Sciences of the United States of America, 2006
Although there is a growing body of evidence that different amyloidoses may have a similar molecular mechanism in common, the many details of this mechanism are not understood. In this study, we propose that there is a common molecular structure of the primary agents of these diseases, namely a small oligomer of Perutz's cylindrical double--stranded subunit for polyglutamine and that this structure, which contains a central water-filled core, can spontaneously integrate into the bilayers of membranes to form aqueous pores. We suggest that this ability to produce permeable channels in appropriate neuronal membranes is a key element in the toxicity of the -amyloids. One strong criterion for the stability of the Perutz structure for an amyloid is that it contain Ϸ40 or more amino acid residues. We show here that the neurotoxic A amyloids 1-40 and 1-42, related to Alzheimer's disease, spontaneously enter the membranes of intact erythrocytes and cause their lysis but that A 1-38 and A 1-35, which are not neurotoxic, have no observable effects on erythrocytes, supporting our proposal. Other aspects of the proposed mechanism of cytotoxicity of the -amyloids are explored. Alzheimer's disease ͉ neurodegeneration ͉ Parkinson's disease Conflict of interest statement: No conflicts declared.
Biochemistry, 2012
Among the growing number of membrane protein structures in the Protein Data Bank, there are many transmembrane domains that appear to be native-like; at the same time, there are others that appear to have less than complete native-like character. Hence, there is an increasing need for validation tools that distinguish native-like from non-native-like structures. Membrane mimetics used in protein structural characterizations differ in numerous physicochemical properties from native membranes and provide many opportunities for introducing nonnative-like features into membrane protein structures. One possible approach for validating membrane protein structures is based on the use of glycine residues in transmembrane domains. Here, we have reviewed the membrane protein structure database and identified a set of benchmark proteins that appear to be native-like. In these structures, conserved glycine residues rarely face the lipid interstices, and many of them participate in close helix−helix packing. Glycine-based validation allowed the identification of non-native-like features in several membrane proteins and also shows the potential for verifying the native-like character for numerous other membrane protein structures.
Amyloid ion channels: A common structural link for protein-misfolding disease
Proceedings of The National Academy of Sciences, 2005
Protein conformational diseases, including Alzheimer's, Huntington's, and Parkinson's diseases, result from protein misfolding, giving a distinct fibrillar feature termed amyloid. Recent studies show that only the globular (not fibrillar) conformation of amyloid proteins is sufficient to induce cellular pathophysiology. However, the 3D structural conformations of these globular structures, a key missing link in designing effective prevention and treatment, remain undefined as of yet. By using atomic force microscopy, circular dichroism, gel electrophoresis, and electrophysiological recordings, we show here that an array of amyloid molecules, including amyloid-(1-40), ␣-synuclein, ABri, ADan, serum amyloid A, and amylin undergo supramolecular conformational change. In reconstituted membranes, they form morphologically compatible ion-channel-like structures and elicit single ion-channel currents. These ion channels would destabilize cellular ionic homeostasis and hence induce cell pathophysiology and degeneration in amyloid diseases.
Among the growing number of membrane protein structures in the Protein Data Bank, there are many transmembrane domains that appear to be native-like; at the same time, there are others that appear to have less than complete native-like character. Hence, there is an increasing need for validation tools that distinguish native-like from non-native-like structures. Membrane mimetics used in protein structural characterizations differ in numerous physicochemical properties from native membranes and provide many opportunities for introducing nonnative-like features into membrane protein structures. One possible approach for validating membrane protein structures is based on the use of glycine residues in transmembrane domains. Here, we have reviewed the membrane protein structure database and identified a set of benchmark proteins that appear to be native-like. In these structures, conserved glycine residues rarely face the lipid interstices, and many of them participate in close helix−helix packing. Glycine-based validation allowed the identification of non-native-like features in several membrane proteins and also shows the potential for verifying the native-like character for numerous other membrane protein structures.
Biophysical Journal, 2009
In Alzheimer's disease, calcium permeability through cellular membranes appears to underlie neuronal cell death. It is increasingly accepted that calcium permeability involves toxic ion channels. We modeled Alzheimer's disease ion channels of different sizes (12-mer to 36-mer) in the lipid bilayer using molecular dynamics simulations. Our Ab channels consist of the solid-state NMR-based U-shaped b-strand-turn-b-strand motif. In the simulations we obtain ion-permeable channels whose subunit morphologies and shapes are consistent with electron microscopy/atomic force microscopy. In agreement with imaged channels, the simulations indicate that b-sheet channels break into loosely associated mobile b-sheet subunits. The preferred channel sizes (16-to 24-mer) are compatible with electron microscopy/atomic force microscopy-derived dimensions. Mobile subunits were also observed for b-sheet channels formed by cytolytic PG-1 b-hairpins. The emerging picture from our large-scale simulations is that toxic ion channels formed by b-sheets spontaneously break into loosely interacting dynamic units that associate and dissociate leading to toxic ionic flux. This sharply contrasts intact conventional gated ion channels that consist of tightly interacting a-helices that robustly prevent ion leakage, rather than hydrogen-bonded b-strands. The simulations suggest why conventional gated channels evolved to consist of interacting a-helices rather than hydrogen-bonded b-strands that tend to break in fluidic bilayers. Nature designs folded channels but not misfolded toxic channels.
In Alzheimer's disease, calcium permeability through cellular membranes appears to underlie neuronal cell death. It is increasingly accepted that calcium permeability involves toxic ion channels. We modeled Alzheimer's disease ion channels of different sizes (12-mer to 36-mer) in the lipid bilayer using molecular dynamics simulations. Our Ab channels consist of the solid-state NMR-based U-shaped b-strand-turn-b-strand motif. In the simulations we obtain ion-permeable channels whose subunit morphologies and shapes are consistent with electron microscopy/atomic force microscopy. In agreement with imaged channels, the simulations indicate that b-sheet channels break into loosely associated mobile b-sheet subunits. The preferred channel sizes (16-to 24-mer) are compatible with electron microscopy/atomic force microscopy-derived dimensions. Mobile subunits were also observed for b-sheet channels formed by cytolytic PG-1 b-hairpins. The emerging picture from our large-scale simulations is that toxic ion channels formed by b-sheets spontaneously break into loosely interacting dynamic units that associate and dissociate leading to toxic ionic flux. This sharply contrasts intact conventional gated ion channels that consist of tightly interacting a-helices that robustly prevent ion leakage, rather than hydrogen-bonded b-strands. The simulations suggest why conventional gated channels evolved to consist of interacting a-helices rather than hydrogen-bonded b-strands that tend to break in fluidic bilayers. Nature designs folded channels but not misfolded toxic channels.
Clinical and Experimental Pharmacology and Physiology, 2002
1. Protein-membrane interaction includes the interaction of proteins with intrinsic receptors and ion transport pathways and with membrane lipids. Several hypothetical interaction models have been reported for peptide-induced membrane destabilization, including hydrophobic clustering, electrostatic interaction, electrostatic followed by hydrophobic interaction, wedge ؋ type incorporation and hydrophobic mismatch. 2. The present review focuses on the hypothesis of protein interaction with lipid membranes of those unchaperoned positively charged and misfolded proteins that have hydrophobic regions. We advance the hypothesis that protein misfolding that leads to the exposure of hydrophobic regions of proteins renders them potentially cytotoxic. Such proteins include prion, amyloid  protein (A  P), amylin, calcitonin, serum amyloid and C-type natriuretic peptides. These proteins have the ability to interact with lipid membranes, thereby inducing membrane damage and cell malfunction. 3. We propose that the most significant mechanism of membrane damage induced by hydrophobic misfolded proteins is mediated via the formation of ion channels. The hydrophobicity based toxicity of several proteins linked to neurodegenerative pathologies is similar to those observed for antibacterial toxins and viral proteins. 4. It is hypothesized that the membrane damage induced by amyloids, antibacterial toxins and viral proteins represents a common mechanism for cell malfunction, which underlies the associated pathologies and cytotoxicity of such proteins.
Membrane proteins: from bench to bits
Biochemical Society transactions, 2011
Membrane proteins currently receive a lot of attention, in large part thanks to a steady stream of highresolution X-ray structures. Although the first few structures showed proteins composed of tightly packed bundles of very hydrophobic more or less straight transmembrane α-helices, we now know that helix-bundle membrane proteins can be both highly flexible and contain transmembrane segments that are neither very hydrophobic nor necessarily helical throughout their lengths. This raises questions regarding how membrane proteins are inserted into the membrane and fold in vivo, and also complicates life for bioinformaticians trying to predict membrane protein topology and structure.
The Pathogenic A116V Mutation Enhances Ion-Selective Channel Formation by Prion Protein in Membranes
Biophysical journal, 2016
Prion diseases are a group of fatal neurodegenerative disorders that afflict mammals. Misfolded and aggregated forms of the prion protein (PrP(Sc)) have been associated with many prion diseases. A transmembrane form of PrP favored by the pathogenic mutation A116V is associated with Gerstmann-Sträussler-Scheinker syndrome, but no accumulation of PrP(Sc) is detected. However, the role of the transmembrane form of PrP in pathological processes leading to neuronal death remains unclear. This study reports that the full-length mouse PrP (moPrP) significantly increases the permeability of living cells to K(+), and forms K(+)- and Ca(2+)-selective channels in lipid membranes. Importantly, the pathogenic mutation A116V greatly increases the channel-forming capability of moPrP. The channels thus formed are impermeable to sodium and chloride ions, and are blocked by blockers of voltage-gated ion channels. Hydrogen-deuterium exchange studies coupled with mass spectrometry (HDX-MS) show that up...