Secreted Cysteine-Rich Repeat Proteins "SCREPs": A Novel Multi-Domain Architecture.

Michael Maxwell,Mehdi Mobli,Eivind A B Undheim

doi:10.3389/fphar.2018.01333

Abstract

Peptide toxins isolated from animal venom secretions have proven to be useful pharmacological tools for probing the structure and function of a number of molecular receptors. Their molecular structures are stabilized by posttranslational formation of multiple disulfide bonds formed between sidechain thiols of cysteine residues, resulting in high thermal and chemical stability. Many of these peptides have been found to be potent modulators of ion channels, making them particularly influential in this field. Recently, several peptide toxins have been described that have an unusual tandem repeat organization, while also eliciting a unique pharmacological response toward ion channels. Most of these are two-domain peptide toxins from spider venoms, such as the double-knot toxin (DkTx), isolated from the Earth Tiger tarantula (Haplopelma schmidti). The unusual pharmacology of DkTx is its high avidity for its receptor (TRPV1), a property that has been attributed to a bivalent mode-of-action. DkTx has subsequently proven a powerful tool for elucidating the structural basis for the function of the TRPV1 channel. Interestingly, all tandem repeat peptides functionally characterized to date share this high avidity to their respective binding targets, suggesting they comprise an unrecognized structural class of peptides with unique structural features that result in a characteristic set of pharmacological properties. In this article, we explore the prevalence of this emerging class of peptides, which we have named Secreted, Cysteine-rich REpeat Peptides, or “SCREPs.” To achieve this, we have employed data mining techniques to extract SCREP-like sequences from the UniProtKB database, yielding approximately sixty thousand candidates. These results indicate that SCREPs exist within a diverse range of species with greatly varying sizes and predicted fold types, and likely include peptides with novel structures and unique modes of action. We present our approach to mining this database for discovery of novel ion-channel modulators and discuss a number of “hits” as promising leads for further investigation. Our database of SCREPs thus constitutes a novel resource for biodiscovery and highlights the value of a data-driven approach to the identification of new bioactive pharmacological tools and therapeutic lead molecules.

Highlights

The need for more advanced therapeutics has driven the recent growth in interest toward the use of natural sources in drug discovery and development programs (Newman and Cragg, 2016)
Some major domain types found within toxins throughout a diverse taxonomic range include: the inhibitor cystine knot (ICK) which is included among the “knottins” (Gracy et al, 2008), the Kunitz/Bovine pancreatic trypsin inhibitor (BPTI) (Ascenzi et al, 2003), the Kazal-like domain (Friedrich et al, 1993), the whey acidic protein (WAP) domain (Hennighausen and Sippel, 1982), the ShKT-like domain (Castaneda et al, 1995), and the phospholipase A2 (PLA2) enzymatic domain (Rigoni et al, 2005; Lavergne et al, 2015)
Our results reveal that SCREPs comprise a surprisingly high number of diverse protein sequences, a portion of which display high levels of sequence identity with previously studied ion-channel impairing toxins

Summary

INTRODUCTION

The need for more advanced therapeutics has driven the recent growth in interest toward the use of natural sources in drug discovery and development programs (Newman and Cragg, 2016). One approach toward structural classification of DRDs, is by clustering the spatial arrangement of secondary structural features This has led to the identification of 41 unique fold groups, identified from 963 domain representatives (Cheek et al, 2006). Within these major fold groups exist numerous examples of venom derived DRDs. Some major domain types found within toxins throughout a diverse taxonomic range include: the inhibitor cystine knot (ICK) which is included among the “knottins” (Gracy et al, 2008), the Kunitz/Bovine pancreatic trypsin inhibitor (BPTI) (Ascenzi et al, 2003), the Kazal-like domain (Friedrich et al, 1993), the whey acidic protein (WAP) domain (Hennighausen and Sippel, 1982), the ShKT-like domain (Castaneda et al, 1995), and the phospholipase A2 (PLA2) enzymatic domain (Rigoni et al, 2005; Lavergne et al, 2015). Our results reveal that SCREPs comprise a surprisingly high number of diverse protein sequences, a portion of which display high levels of sequence identity with previously studied ion-channel impairing toxins

A DATA DRIVEN APPROACH IN PROTEIN BIO-DISCOVERY

Findings

CONCLUSION