@article{4179,
  keywords = {Protein Processing, Post-Translational, Peptides, Aspartic Acid, Bacillales, Protein D-Aspartate-L-Isoaspartate Methyltransferase, Thermobifida},
  author = {Li Cao and Moshe Beiser and Joseph Koos and Margarita Orlova and Hader Elashal and Hendrik Schr{\"o}der and A James Link},
  title = {Cellulonodin-2 and Lihuanodin: Lasso Peptides with an Aspartimide Post-Translational Modification.},
  abstract = { <p>Lasso peptides are a family of ribosomally synthesized and post-translationally modified peptides (RiPPs) defined by their threaded structure. Besides the class-defining isopeptide bond, other post-translational modifications (PTMs) that further tailor lasso peptides have been previously reported. Using genome mining tools, we identified a subset of lasso peptide biosynthetic gene clusters (BGCs) that are colocalized with genes encoding protein l-isoaspartyl methyltransferase (PIMT) homologues. PIMTs have an important role in protein repair, restoring isoaspartate residues formed from asparagine deamidation to aspartate. Here we report a new function for PIMT enzymes in the post-translational modification of lasso peptides. The PIMTs associated with lasso peptide BGCs first methylate an l-aspartate side chain found within the ring of the lasso peptide. The methyl ester is then converted into a stable aspartimide moiety, endowing the lasso peptide ring with rigidity relative to its unmodified counterpart. We describe the heterologous expression and structural characterization of two examples of aspartimide-modified lasso peptides from thermophilic Gram-positive bacteria. The lasso peptide cellulonodin-2 is encoded in the genome of actinobacterium , while lihuanodin is encoded in the genome of firmicute . Additional genome mining revealed PIMT-containing lasso peptide BGCs in 48 organisms. In addition to heterologous expression, we have reconstituted PIMT-mediated aspartimide formation in vitro, showing that lasso peptide-associated PIMTs transfer methyl groups very rapidly as compared to canonical PIMTs. Furthermore, in stark contrast to other characterized lasso peptide PTMs, the methyltransferase functions only on lassoed substrates.</p> },
  year = {2021},
  journal = {J Am Chem Soc},
  volume = {143},
  pages = {11690-11702},
  month = {2021 Aug 04},
  issn = {1520-5126},
  doi = {10.1021/jacs.1c05017},
  language = {eng},
}