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Pseudokinases can catalyse peptide cyclization through thioether crosslinking.

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Pseudokinases, typically inactive enzymes, unexpectedly catalyze peptide cyclization for thioether bond formation. This discovery reveals a novel function for the protein-kinase fold in biosynthesis.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Protein-kinase-like superfamily proteins are vital for cellular signaling via phosphorylation.
  • Pseudokinases are related proteins lacking canonical kinase activity, with some exhibiting unique catalytic functions.
  • Ribosomally synthesized and post-translationally modified peptides, such as thioamitides and lanthipeptides, involve complex modifications.

Purpose of the Study:

  • To investigate the enzymatic activity of pseudokinases beyond phosphorylation.
  • To identify and characterize the peptide cyclization activity of specific pseudokinases (TvaE and SacE).
  • To explore the mechanism of (ene)thioether residue formation catalyzed by these pseudokinases.

Main Methods:

  • Biosynthetic investigations of thioamitides and lanthipeptides.
  • Biochemical characterization and heterologous expression of pseudokinases.
  • Co-crystallization, computational analysis, and site-specific mutagenesis.
  • Genome mining and isotope labeling studies.

Main Results:

  • Pseudokinases TvaE and SacE were found to possess peptide cyclization activity, forming (ene)thioether residues.
  • The study identified dedicated cyclase activity in unsaturated 2-aminovinyl-cysteine formation and explored saturated lanthionine formation.
  • A common catalytic mechanism involving Michael addition for crosslinking was elucidated, distinct from canonical protein kinases.

Conclusions:

  • The protein-kinase fold can be repurposed for novel catalytic functions, such as peptide cyclization.
  • Pseudokinases can act as cyclases, catalyzing Michael addition for thioether crosslinking.
  • This finding expands the known functional repertoire of pseudokinases and protein-kinase-like proteins.