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Stabilization of TRAIL, an all-beta-sheet multimeric protein, using computational redesign.

Almer M van der Sloot1, Margaret M Mullally, Gregorio Fernandez-Ballester

  • 1Department of Pharmaceutical Biology, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.

Protein Engineering, Design & Selection : PEDS
|October 16, 2004
PubMed
Summary

Researchers computationally redesigned the cytokine TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) to improve its thermal stability. This enhanced stability is crucial for therapeutic applications and protein production, demonstrating a novel approach for protein engineering.

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Area of Science:

  • Biochemistry
  • Protein Engineering
  • Structural Biology

Background:

  • Protein thermal stability is critical for therapeutic efficacy, influencing pharmacokinetics, pharmacodynamics, and shelf-life.
  • The cytokine TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a therapeutically relevant trimeric protein with an all-beta-sheet structure.

Purpose of the Study:

  • To computationally redesign the TRAIL protein to enhance its thermal stability.
  • To explore modifications of monomer subunits and monomer-monomer interfaces for improved protein stability.

Main Methods:

  • Utilized TNF ligand family alignment information and the PERLA computational design algorithm.
  • Focused redesign efforts on non-conserved residues to optimize computational resource usage.
  • Experimentally validated thermal stability using far-UV circular dichroism thermal denaturation.

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Main Results:

  • Several designed mutants exhibited significantly increased thermal stability compared to wild-type TRAIL.
  • A double mutant demonstrated an 8°C increase in apparent T(m) and retained biological activity after heat treatment.
  • Stabilization was achieved through modifications at the monomer subunit or monomer-monomer interface.

Conclusions:

  • Computational redesign successfully improved the thermal stability of the multimeric TRAIL protein.
  • This study presents the first instance of enhancing the stability of a large, multimeric beta-sheet protein via computational redesign.
  • The employed methodology is applicable to other multimeric proteins, including members of the TNF ligand family.