Abstract
Proteins of the ShK superfamily are characterized by a small conserved domain (ShKT), first discovered in small venom peptides produced by sea anemones, and acting as specific inhibitors of voltage-dependent and calcium-activated K+ channels. The ShK superfamily includes both small toxic peptides and larger multifunctional proteins with various functions. ShK toxins are often important components of animal venoms, where they perform different biological functions including neurotoxic and immunosuppressive effects. Given their high specificity and effectiveness, they are currently regarded as promising pharmacological lead compounds for the treatment of autoimmune diseases. Here, we report on the molecular analysis of ShKT domain containing proteins produced by the Mediterranean vampire snail Cumia reticulata, an ectoparasitic gastropod that feeds on benthic fishes. The high specificity of expression of most ShK transcripts in salivary glands identifies them as relevant components of C. reticulata venom. These ShK proteins display various structural architectures, being produced either as single-domain secretory peptides, or as larger proteins combining the ShKT with M12 or CAP domains. Both ShKT-containing genes and their internal ShKT domains undergo frequent duplication events in C. reticulata, ensuring a high level of variability that is likely to play a role in increasing the range of their potential molecular targets.
Highlights
The ShK toxin (ShKT) is a potent potassium (K+ ) channel blocker, which was originally isolated from the Caribbean sea anemone Stichodactyla helianthus [1] and subsequently chemically synthesized [2]
While some ShKT domain-containing proteins have been reported in a previous transcriptomic analysis on the secretory tissues of the foregut in C. reticulata [24], we provide here an improved characterization of their full-length sequences, with an in silico assessment of their correctness
Domain repeats are widespread in eukaryotic genomes where they are thought to arise via tandem duplications within a gene, which may involve single domains or units containing several repeated domains, increasing the rate of generation of multiple repeats [68,69,70,71]
Summary
The ShK toxin (ShKT) is a potent potassium (K+ ) channel blocker, which was originally isolated from the Caribbean sea anemone Stichodactyla helianthus [1] and subsequently chemically synthesized [2]. Toxins 2019, 11, 106 channels are ubiquitous tetrameric membrane proteins that regulate membrane potential and calcium signaling in diverse cell types, including those involved in both innate and adaptive immune response. Given their widespread distribution and their central physiological role in all living organisms, K+ channels are the target of hundreds of toxins that generally contain between 18 and. A recent classification includes ShK in the sea anemone type 1 potassium channel toxin family [8]. Molecular modelling coupled with mutational analyses has identified Lys as a key residue for the blockage of the K+ channel, since this residue is able to penetrate and occlude the pore of the channel [9,10], while Ser, Lys and Tyr have been demonstrated to be responsible for the binding of ShK to KV channels in rat brain [3]
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