Funktionelle Proteine aus kurzen Peptiden: 50 Jahre nach Margaret Dayhoffs Hypothese

Mutationen und Veränderungen in der Umgebung eines Proteins sind bekannt dafür, potenziell Fehlfaltungen und Aggregation wie Amyloidbildung zu verursachen. Derartige Einflüsse können allerdings auch neue Interaktionen bewirken, die zur Polymerisation gefalteter Proteine führen. Im Unterschied zur Aggregation können solche Vorgänge aber auch ohne Fehlfaltungen ablaufen. Um diesen Unterschied hervorzuheben, bezeichnen wir sie als Agglomeration. Dieser Begriff umfasst die amorphe Zusammenlagerung gefalteter Proteine wie auch deren ein‐, zwei‐ und dreidimensionale Polymerisation. Wir möchten auf die bemerkenswerte Fähigkeit symmetrischer Homooligomere hinweisen, sogar infolge einzelner Oberflächenmutationen zu agglomerieren. Wir erörtern des Weiteren die ambivalente Natur dieser Eigenschaft: Durch Agglomeration entstandene anomale Ansammlungen können einerseits zum Entstehen von Krankheiten beitragen, sind aber andererseits auch für die zelluläre Anpassung verantwortlich und können zudem für das zielgerichtete Design neuer Biomaterialien genutzt werden.

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Infinite Ansammlungen gefalteter Proteine im Kontext von Evolution, Krankheiten und Proteinentwicklung

Garcia‐Seisdedos

Villegas

Levy

2019

Angewandte Chemie

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Gene Fusion and Directed Evolution to Break Structural Symmetry and Boost Catalysis by an Oligomeric C−C Bond‐Forming Enzyme

Kunzendorf

Crotti

et al. 2021

Angewandte Chemie

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Gene duplication and fusion are among the primary natural processes that generate new proteins from simpler ancestors. Here we adopted this strategy to evolve a promiscuous homohexameric 4-oxalocrotonate tautomerase (4-OT) into an efficient biocatalyst for enantioselective Michael reactions. We first designed a tandem-fused 4-OT to allow independent sequence diversification of adjacent subunits by directed evolution. This fused 4-OT was then subjected to eleven rounds of directed evolution to give variant 4-OT(F11), which showed an up to 320-fold enhanced activity for the Michael addition of nitromethane to cinnamaldehydes. Crystallographic analysis revealed that 4-OT(F11) has an unusual asymmetric trimeric architecture in which one of the monomers is flipped 180°relative to the others. This gene duplication and fusion strategy to break structural symmetry is likely to become an indispensable asset of the enzyme engineering toolbox, finding wide use in engineering oligomeric proteins.

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Infinite Assembly of Folded Proteins in Evolution, Disease, and Engineering

2019

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Mutations and changes in a protein's environment are well characterized for their potential to induce misfolding and aggregation, including amyloid formation. Alternatively, such perturbations can trigger new interactions leading to the polymerization of folded proteins. In contrast to aggregation, this process does not require misfolding and to mark this difference, we refer to it as agglomeration. This term encompasses the amorphous assembly of folded proteins as well as their folded-state polymerization in one-, two-, or three-dimensions. We stress the remarkable potential of symmetric homo-oligomers to agglomerate even by single surface point mutations, and we review the double-edged nature of this potential: how aberrant assemblies resulting from agglomeration can lead to disease, but also how agglomeration can serve in cellular adaptation and be exploited for the rational design of novel biomaterials.

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Funktionelle Proteine aus kurzen Peptiden: 50 Jahre nach Margaret Dayhoffs Hypothese

Cited by 5 publications

References 56 publications

Infinite Ansammlungen gefalteter Proteine im Kontext von Evolution, Krankheiten und Proteinentwicklung

Infinite Ansammlungen gefalteter Proteine im Kontext von Evolution, Krankheiten und Proteinentwicklung

Gene Fusion and Directed Evolution to Break Structural Symmetry and Boost Catalysis by an Oligomeric C−C Bond‐Forming Enzyme

Infinite Assembly of Folded Proteins in Evolution, Disease, and Engineering

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