Extending the Peptide/Protein Interaction Paradigm to a Protein/Protein Engagement Model in RiPP Biosynthesis

Abstract

Enzymatic post-translational modification of small precursor peptides generates a wide diversity of bioactive peptidic natural products. The interaction between the precursor peptide and the peptide modifying enzyme relies on recognition of the N-terminal region of the precursor peptide─termed the leader peptide─by the modifying enzyme. In this study, we describe a model for the recognition of atypically long and highly structured nitrile hydratase-like leader peptides (NHLPs) by an azoline forming YcaO cyclodehydratase. Predicated upon the unique structure of NHLPs, the binding model relies on protein/protein interactions between higher-order secondary and tertiary structures of the NHLP and the modifying enzyme. In light of previous findings, we report that different modifying enzymes bind to different molecular surfaces of the NHLPs. These findings illustrate the modularity of different NHLP structural features and how fine-tuning of intermolecular interactions is necessary for efficient catalysis.