7LCW

Aspartimidylated Lasso Peptide Lihuanodin

Summary for 7LCW

• Entry DOI: 10.2210/pdb7lcw/pdb
• NMR Information: BMRB: 30843
• Descriptor: Lasso Peptide Lihuanodin (1 entity in total)
• Functional Keywords: post-translational modification, unknown function
• Biological source: Lihuaxuella thermophila
• Total number of polymer chains: 1
• Total formula weight: 1753.78

Authors

Link, A.J.,Cao, L. (deposition date: 2021-01-11, release date: 2021-07-28, Last modification date: 2024-05-15)

Primary citation

Cao, L.,Beiser, M.,Koos, J.D.,Orlova, M.,Elashal, H.E.,Schroder, H.V.,Link, A.J.
Cellulonodin-2 and Lihuanodin: Lasso Peptides with an Aspartimide Post-Translational Modification.
J.Am.Chem.Soc., 143:11690-11702, 2021

PubMed Abstract: 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.

PubMed: 34283601
DOI: 10.1021/jacs.1c05017

Experimental method

SOLUTION NMR