Late Lunch Talk: Secreted cysteine-rich repeat proteins “SCREPs”: a novel multi-domain architecture
Late Lunch Talk by Michael Maxwell
Peptide toxins isolated from animal venoms have proven to be useful pharmacological tools, demonstrating great capability to act as stable, highly selective, and potent ligands towards therapeutically relevant targets such as ion channels. Most peptide toxins display a single domain type architecture, where their molecular structure is stabilised by posttranslational formation of multiple intramolecular disulfide bonds. Recently, toxins consisting of a tandem repeat type domain organisation were discovered in spider venoms. These two-domain toxins demonstrate unique pharmacology that is driven by a bivalent mode of interaction with their molecular targets, suggesting peptides with similar tandem repeat toxin-like domain architecture may be a source of interesting molecules. Here, I will show that these two-domain spider toxins are part of a broad class of biomolecules that include a large group (≈120,000) of secreted, cysteine-rich repeat proteins (SCREPs). I will present both the methodology and results of the datamining approach used to identify SCREPs, including the discovery of a novel SCREP, namely double-ICK3 from the venom of the remipede Xibalbanus tulumensis. Recombinant expression of this peptide followed by high-resolution structural characterisation by NMR and pharmacological screening revealed that double-ICK3 is the third addition of venom-derived ion channel impairing SCREPs, but the first to modulate the activity of ryanodine receptors (RyR). This toxin demonstrates the exciting potential of SCREPs as a novel resource, enabling the investigation of multivalent interactions between peptide ligands and their molecular targets. It also highlights the usefulness of bioinformatic tools commonly used for sequence annotation and molecular evolution analyses in exploring the rapidly expanding protein sequence space and supporting efforts toward the rational design of novel therapeutics.