ScrepYard: an online resource for disulfide-stabilised tandem repeat peptides

Abstract

Receptor avidity through multivalency is a highly sought-after property of ligands. While readily available in nature in the form of bivalent antibodies, this property remains challenging to engineer in synthetic molecules. The discovery of several bivalent venom peptides containing two homologous and independently folded domains (in a tandem repeat arrangement) has provided a unique opportunity to better understand the underpinning design of multivalency in multimeric biomolecules, as well as how naturally occurring multivalent ligands can be identified. In previous work we classified these molecules as a larger class termed secreted cysteine-rich repeat-proteins (SCREPs). Here, we present an online resource; ScrepYard, designed to assist researchers in identification of SCREP sequences of interest and to aid in characterizing this emerging class of biomolecules. Analysis of sequences within the ScrepYard reveals that two-domain tandem repeats constitute the most abundant SCREP domain architecture, while the interdomain linker regions connecting the ordered domains are found to be abundant in amino acids with short or polar sidechains and contain an unusually high abundance of proline residues. Finally, we demonstrate the utility of ScrepYard as a virtual screening tool for discovery of putatively multivalent peptides, by using it as a resource to identify a previously uncharacterised serine protease inhibitor and confirm its predicated activity using an enzyme assay.

Identification of a sensory neuron Cav2.3 inhibitor within a new superfamily of macro-conotoxins

“…In general, the size of macroconotoxins likely confers specific properties not available to small toxins. For instance, larger toxins could participate in multivalent interactions with their targets, as noted for con-ikot-ikot and recently pointed out for bivalent venom peptides containing two homologous domains connected by an interdomain linker (46). It is conceivable that non-covalent dimers, as seen in Mu8.1, could also allow interaction with, e.g., two identical subunits of a molecular target.…”