Post‐translationally modified neuropeptides from Conus venoms

Abstract

Predatory cone snails (genus Conus) comprise what is arguably the largest living genus of marine animals (500 species). All Conus use complex venoms to capture prey and for other biological purposes. Most biologically active components of these venoms are small disulfide-rich peptides, generally 7±35 amino acids in length. There are probably of the order of 100 different peptides expressed in the venom of each of the 500 Conus species [1,2]. Peptide sequences diverge rapidly between Conus species, resulting in a distinct peptide complement for each species. Thus, the genus as a whole has probably generated < 50 000 different peptides, which can be organized into families and superfamilies with shared sequence elements [3]. In this minireview, we provide a brief overview of the neuropharmacological, molecular and cell-biological aspects of the Conus peptides. However, the major focus of the review will be the remarkable array of post-translational modifications found in these peptides.

Optimized deep-targeted proteotranscriptomic profiling reveals unexplored Conus toxin diversity and novel cysteine frameworks

“…As a result of speciation, a high rate of hypermutations, and a remarkable number of posttranslational modifications, little overlap of conopeptides between Conus species has been observed (11,12), which has led to an estimation of >70,000 pharmacologically active conopeptides although fewer than 1% have been characterized to date (13). The precursor form of conotoxins is composed of three distinct regions: a highly conserved N-terminal endoplasmic reticulum (ER) signal region (used to classify the toxins into gene superfamilies), a central proregion, and a hypervariable mature region, typically between 10 and 35 amino acids long, characterized by conserved cysteine patterns and connectivities (14)(15)(16).…”

Fbxo45-mediated degradation of the tumor-suppressor Par-4 regulates cancer cell survival

“…29 Par-4 is a tumor suppressor and a critical regulator of tumor cell survival. 14,26 Subtle changes in regulation and alteration of Par-4 expression and localization may impact its biological function as a pro-apoptotic protein.…”

Evolution of Matrix and Bone γ-Carboxyglutamic Acid Proteins in Vertebrates

“…Some of them have been identified in previous studies (48,52,53), but one is described for the first time in this work (the ANXF putative peptide cleavage site) although it has already been observed in the past. 4 This site is present in MGP and would cleave what is considered the core of the protein (the C terminus containing the Gla domain) from the N terminus containing the phosphorylation and the GGCX domains. The purification of low molecular weight MGP fragments identifying a cleavage site after the asparagine (N) residue of the ANXF domain further confirmed the post-translational proteolytic processing of MGP at this site (12).…”

“…In other words, duplicates evolve to acquire new functions. Several more speculative lines of evidence for BGP being a duplicate of MGP have been collected: 1) the presence of a MGP-like immunoreactive protein has been observed in lamprey (the more ancient species 4 tested), whereas BGP was not detected 7 ; 2) MGP is associated with cartilage, which appeared with the first vertebrates, whereas BGP is only associated with bone, a structure that appeared later in evolution; and 3) BGP seems to be better conserved than MGP.…”