Analysis of the sequence and structural features of the left‐handed β‐helical fold

Choi, Jay H.; Govaerts, Cédric; May, Barnaby C. H.; Cohen, Fred E.

doi:10.1002/prot.22051

Cited by 19 publications

(41 citation statements)

References 41 publications

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“…This structure arises in a number of bacterial enzymes, usually in a trimer configuration (type II, with 18 residues per helical turn in an ideal structure), and in some insect anti-freeze proteins (type I, with 15 residues per helical turn in an ideal structure). 10,11 For prions, a trimer of b-helix containing monomers has been proposed as a candidate for the repeat units of a two dimensional crystal, 8,12 although a competing model with spiraling b sheet structure has also been developed which agrees with much of the available data. 13,14 Fibrils can be formed from LHBH models by stacking the oligomers.…”

Section: Introductionsupporting

confidence: 69%

“…We have also assessed three stability characteristics for the CLHBHs to be compared with several of the type II LHBH PDB proteins. 11 Figure 8 shows the number of side-chain-to-sidechain hydrogen bonds, volume packing fraction and a frustration index (counting the number of satisfied polar/charged and hydrophobic interactions with water). We find these side-chain/side-chain hydrogen bonds to be predominantly at the corners of known structures, with an average of about 2 per turn.…”

Section: Resultsmentioning

confidence: 99%

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Left handed β helix models for mammalian prion fibrils

Kuneš

Clark

Cox

et al. 2008

Prion

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We propose models for in vitro grown mammalian prion protein fibrils based upon left handed beta helices formed both from the N-terminal and C-terminal regions of the proteinase resistant infectious prion core. The C-terminal threading onto a b-helical structure is almost uniquely determined by fixing the cysteine disulfide bond on a helix corner. In comparison to known left handed helical peptides, the resulting model structures have similar stability attributes including relatively low root mean square deviations in all atom molecular dynamics, substantial side-chainto-side-chain hydrogen bonding, good volume packing fraction, and low hydrophilic/hydrophobic frustration. For the N-terminus, we propose a new threading of slightly more than two turns, which improves upon the above characteristics relative to existing three turn b-helical models. The N-terminal and C-terminal beta helices can be assembled into eight candidate models for the fibril repeat units, held together by large hinge (order 30 residues) domain swapping, with three amenable to fibril promoting domain swapping via a small (five residue) hinge on the N-terminal side. Small concentrations of the metastable C-terminal b helix in vivo might play a significant role in templating the infectious conformation and in enhancing conversion kinetics for inherited forms of the disease and explain resistance (for canines) involving hypothesized coupling to the methionine 129 sulfur known to play a role in human disease.

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Section: Introductionsupporting

confidence: 69%

Section: Resultsmentioning

confidence: 99%

Left handed β helix models for mammalian prion fibrils

Kuneš

Clark

Cox

et al. 2008

Prion

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“…Thus, the trends we have uncovered should contribute to the complex network of factors that determines protein folding preferences, [34] and may be of particular significance in families that are rich in parallel-b-sheet secondary structure, such as leucine-rich repeat proteins [35] and parallel-b-helix proteins. [36] Previous work suggests that antiparallel-b-sheets are less susceptible to length-dependent stabilization than we find to be true of parallel b sheets. [19] This apparent difference between strand topologies may underlie an apparent preference for parallel orientations among intermolecular b-sheet interactions within amyloid assemblies.…”

Section: Methodscontrasting

confidence: 58%

Impact of Strand Length on the Stability of Parallel‐β‐Sheet Secondary Structure

et al. 2011

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The thousands of tertiary structural motifs known among natural proteins are built up from a handful of regular secondary structures, mostly a helices and b sheets, which are linked by b turns and larger loops. Sequence-stability relationships for a helices [1][2][3] and for antiparallel b sheets [4][5][6][7] have been widely explored using autonomously folding peptides, an experimental approach that eliminates the potentially confounding influence of a specific tertiary context. In contrast, a minimal parallel b sheet cannot readily be generated within a conventional peptide because the N terminus of one strand is necessarily distant from the C terminus of a neighboring strand. A continuous peptide design for a parallel b sheet would require a long interstrand loop, introducing significant tertiary packing effects or an entropic penalty for folding, either of which would compromise the analysis. Thus, novel strategies are required to elucidate the factors that govern parallel-b-sheet stability. [8,9] Herein we use recently developed tools, including short nonpeptidic units for connecting peptide strands through their C termini, [10,11] to explore a fundamental question: does parallel-b-sheet secondary structure become more stable as the strands grow longer? The a helix is well known to be stabilized by increasing length.[12-15] a-Helix initiation (ordering of the first four residues, to enable formation of the first intrahelical H-bond) entails a large entropic cost, which can be offset by a small but favorable energetic gain from propagation (incorporation of individual residues into a preexisting helix). [16][17][18] The longer the a helix, the larger the net thermodynamic benefit from propagation, if the residues have a favorable helix propensity. In contrast, antiparallel-bsheet secondary structure appears to be subject to an intrinsic limit on strand length. [19] The relationship between strand length and parallel-b-sheet stability has not previously been addressed. This gap in experimentation may underlie the relatively limited theoretical treatment of b-sheet formation, [20][21][22] especially for parallel b sheets, [20] which stands in contrast to the extensive theoretical analysis of a-helical folding. [16][17][18] Herein, we show that parallel b sheets becomes steadily more stable as the strands are lengthened, if the added residues have a high b-sheet propensity.Our experimental design is outlined in Figure 1 a. A diamine segment containing d-proline is used to link two strand-forming peptide segments through their C termini. [10,23] This linker promotes but does not strictly enforce bsheet interactions between attached strands in aqueous solution. The extent of b-sheet formation is monitored by NMR spectroscopy [24,25] by measuring a-proton chemical shifts (dC a H) at "indicator" residues (black dots) within the core segment (black) as the strands are extended incrementally (blue). The indicator residues are insulated from the extension segments by an intervening residue; therefore, changes in dC a H...

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“…This unconventional model has no counterpart among the known protein structures in the PDB database and it does not conform to the definitions that are used to describe parallel β-helical structures. 20,56 Therefore, it is difficult to compare this unusual modeling result with known protein folds or other models for PrP Sc . 12 The tight packing of the PrP 27-30 molecules in the crystal lattice and the inferred locations of the N-linked oligosaccharides and the β-sheet structure led to the idea that PrP 27-30 contains a parallel β-helix at its core.…”

Section: Molecular Modelsmentioning

confidence: 99%