Publikation:

Thermostable WW-Domain Scaffold to Design Functional β-Sheet Miniproteins

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Datum

2024

Autor:innen

Lindner, Christina
Schwegler, Niklas
Timmermann, Lisa
Pham, Truc Lam
Reusche, Vanessa
Thomas, Franziska

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oops

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Deutsche Forschungsgemeinschaft (DFG): 390761711
Deutsche Forschungsgemeinschaft (DFG): 414261058

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Open Access-Veröffentlichung
Open Access Green
Core Facility der Universität Konstanz
NMR Core Facility

Gesperrt bis

30. Juni 2025

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Published

Erschienen in

Journal of the American Chemical Society. ACS Publications. 2024, 146(24), S. 16590-16600. ISSN 0002-7863. eISSN 1520-5126. Verfügbar unter: doi: 10.1021/jacs.4c03498

Zusammenfassung

There has been a recent surge in the design of miniproteins for medicinal chemistry, biomaterial design, or synthetic biology. In particular, there is an interest in peptide scaffolds that fold reliably, predictably, and with solid stability. In this article, we present the design of a highly thermostable WW domain, a three-stranded β-sheet motif, with a superior melting temperature of about 90 °C to serve as a core scaffold onto which receptor-like properties can be grafted. We have performed specific rounds of sequence iteration on a WW-domain consensus sequence to decipher sequence positions that affect structural and, thus, thermal stability. We identified a sequence–structure relationship that yields a highly thermostable WW-domain scaffold. High-resolution NMR spectroscopy was applied, which enabled the identification of structural features at the atomic scale that contribute to this high thermostability. Finally, we grafted the binding motifs of the three WW-domain groups─Group I, Group II/III, and Group IV─and organophosphate and metal binding onto the highly thermostable WW-domain scaffold and obtained thermostable de novo WW domains that indeed display the different binding modes that were intended. The organophosphate-binding WW domains exhibit melting temperatures that are up to 34 K higher than previously reported top-down designs. These results impressively demonstrate that the highly thermostable WW-domain core scaffold is a solid platform for the design of discrete and reliably folding functional β-sheet peptide miniproteins, providing an essential addition to the toolbox of peptide scaffolds previously used in synthetic biology and material design.

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540 Chemie

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ISO 690LINDNER, Christina, Anke FRIEMEL, Niklas SCHWEGLER, Lisa TIMMERMANN, Truc Lam PHAM, Vanessa REUSCHE, Michael KOVERMANN, Franziska THOMAS, 2024. Thermostable WW-Domain Scaffold to Design Functional β-Sheet Miniproteins. In: Journal of the American Chemical Society. ACS Publications. 2024, 146(24), S. 16590-16600. ISSN 0002-7863. eISSN 1520-5126. Verfügbar unter: doi: 10.1021/jacs.4c03498
BibTex
@article{Lindner2024-06-19Therm-70150,
  year={2024},
  doi={10.1021/jacs.4c03498},
  title={Thermostable WW-Domain Scaffold to Design Functional β-Sheet Miniproteins},
  number={24},
  volume={146},
  issn={0002-7863},
  journal={Journal of the American Chemical Society},
  pages={16590--16600},
  author={Lindner, Christina and Friemel, Anke and Schwegler, Niklas and Timmermann, Lisa and Pham, Truc Lam and Reusche, Vanessa and Kovermann, Michael and Thomas, Franziska}
}
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