A toolbox for protein design

Höcker, Birte

doi:10.1038/491204a

Cited by 6 publications

(2 citation statements)

References 9 publications

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“…A global view of the protein universe which incorporates inter-fold relationships can provide examples of efficient and evolutionary viable transitions between very different structures. More particularly, how this universe has, and continues to, evolve can be used to simulate directed evolution approaches to protein design [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Structural Bridges through Fold Space

Edwards

Deane

2015

PLoS Comput Biol

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Several protein structure classification schemes exist that partition the protein universe into structural units called folds. Yet these schemes do not discuss how these units sit relative to each other in a global structure space. In this paper we construct networks that describe such global relationships between folds in the form of structural bridges. We generate these networks using four different structural alignment methods across multiple score thresholds. The networks constructed using the different methods remain a similar distance apart regardless of the probability threshold defining a structural bridge. This suggests that at least some structural bridges are method specific and that any attempt to build a picture of structural space should not be reliant on a single structural superposition method. Despite these differences all representations agree on an organisation of fold space into five principal community structures: all-α, all-β sandwiches, all-β barrels, α/β and α + β. We project estimated fold ages onto the networks and find that not only are the pairings of unconnected folds associated with higher age differences than bridged folds, but this difference increases with the number of networks displaying an edge. We also examine different centrality measures for folds within the networks and how these relate to fold age. While these measures interpret the central core of fold space in varied ways they all identify the disposition of ancestral folds to fall within this core and that of the more recently evolved structures to provide the peripheral landscape. These findings suggest that evolutionary information is encoded along these structural bridges. Finally, we identify four highly central pivotal folds representing dominant topological features which act as key attractors within our landscapes.

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Section: Introductionmentioning

confidence: 99%

Structural Bridges through Fold Space

Edwards

Deane

2015

PLoS Comput Biol

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“…Among other contributions, the development of Rosetta package has provided a valuable tool for structure prediction and design . A very recent breakthrough in the field is represented by the discovery of Baker and colleagues that the juxtaposition of basic secondary structure elements (α‐helices and β‐strands) follows well‐defined rules . These investigations identified three fundamental rules for the preferences of β ℓ β (strand–loop–strand), α ℓ β (helix–loop–strand), and β ℓ α (strand–loop–helix) structural motifs.…”

Section: Introductionmentioning

confidence: 99%

Role of loops connecting secondary structure elements in the stabilization of proteins isolated from thermophilic organisms

et al. 2013

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It has been recently discovered that the connection of secondary structure elements (bb-unit, ba-and ab-units) in proteins follows quite stringent principles regarding the chirality and the orientation of the structural units (Koga et al., Nature 2012;491:222-227). By exploiting these rules, a number of protein scaffolds endowed with a remarkable thermal stability have been designed (Koga et al., Nature 2012;491:222-227). By using structural databases of proteins isolated from either mesophilic or thermophilic organisms, we here investigate the influence of supersecondary associations on the thermal stability of natural proteins. Our results suggest that b-hairpins of proteins from thermophilic organisms are very frequently characterized by shortenings of the loops. Interestingly, this shortening leads to states that display a very strong preference for the most common connectivity of the strands observed in native protein hairpins. The abundance of selective states in these proteins suggests that they may achieve a high stability by adopting a strategy aimed to reduce the possible conformations of the unfolded ensemble. In this scenario, our data indicate that the shortening is effective if it increases the adherence to these rules. We also show that this mechanism may operate in the stabilization of well-known protein folds (thioredoxin and RNase A). These findings suggest that future investigations aimed at defining mechanism of protein stabilization should also consider these effects.

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Critical Role of a Loop at C-Terminal Domain on the Conformational Stability and Catalytic Efficiency of Chondroitinase ABC I

et al. 2015

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We used a combination of protein engineering and spectroscopic methods to investigate the effect of a long length loop on the conformational stability and activity of chondroitinase ABC I. This study involves manipulation of interactions around Asp(689) as a key residue in the central region of the loop containing residues 681-695 located at C-terminal domain of the enzyme. According to the equilibrium unfolding experiments and considering thermodynamic m value and ΔG(H2O), we found that the folded state of H700N, L701T, and H700N/L701T are more compact relative to the folded state of wild-type protein and they become stabilized upon mutation. However, the compactness and stability of other variants are less than those of wild-type protein. According to enzyme activity measurements, we found that the catalytic efficiency of structurally stabilized variants is decreased, while that of destabilized mutants is improved.

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A toolbox for protein design

Cited by 6 publications

References 9 publications

Structural Bridges through Fold Space

Structural Bridges through Fold Space

Role of loops connecting secondary structure elements in the stabilization of proteins isolated from thermophilic organisms

Critical Role of a Loop at C-Terminal Domain on the Conformational Stability and Catalytic Efficiency of Chondroitinase ABC I

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