Poster Presentation The 45th Lorne Conference on Protein Structure and Function 2020

Structural basis for a natural circular permutation in proteins (#338)

Samuel G Nonis 1 2 , Joel Haywood 1 2 , Jason W Schmidberger 1 , Charlie S Bond 1 , Joshua S Mylne 1 2
  1. University of Western Australia, Perth, WA, Australia
  2. The ARC Centre of Excellence of Plant Energy Biology, Perth, WA, Australia

Over 30 years ago, an intriguing post-translational modification was found to be responsible for creating concanavalin A (conA), a carbohydrate-binding protein found in the seeds of jack bean (Canavalia ensiformis), which is commercially used for carbohydrate chromatography. Biosynthesis of conA involves a then unprecedented rearrangement in amino acid sequence, whereby the N-terminal half of the gene-encoded precursor polypeptide is swapped to become the C-terminal half of mature conA. This finding inspired protein engineers to visit artificial circular permutation upon proteins, preceding the discovery of genetic rearrangements that encode circular permutations. To understand the structural basis and purpose for the circular permutation of conA, we generated recombinant jack bean conA precursor (pro-conA) plus C .ensiformis asparaginyl endopeptidase (CeAEP1), a cysteine protease involved in conA maturation, and solved crystal structures for each to 2.1 Å and 2.7 Å, respectively. By reconstituting the biosynthesis of conA in vitro, we prove that CeAEP1 alone can perform the cleavage-coupled transpeptidation to form conA. Circular dichroism thermal melts showed that mature conA is more stable than proconA, revealing a functional purpose for the first known circular permutation, which remains the only type known to occur after translation.