Data_Sheet_4_A toxin-based approach to neuropeptide and peptide hormone discovery.FASTA

Peptide hormones and neuropeptides form a diverse class of bioactive secreted molecules that control essential processes in animals. Despite breakthroughs in peptide discovery, many signaling peptides remain undiscovered. Recently, we demonstrated the use of somatostatin-mimicking toxins from cone snails to identify the invertebrate ortholog of somatostatin. Here, we show that this toxin-based approach can be systematically applied to discover other unknown secretory peptides that are likely to have signaling function. Using large sequencing datasets, we searched for homologies between cone snail toxins and secreted proteins from the snails’ prey. We identified and confirmed expression of five toxin families that share strong similarities with unknown secretory peptides from mollusks and annelids and in one case also from ecdysozoans. Based on several lines of evidence we propose that these peptides likely act as signaling peptides that serve important physiological functions. Indeed, we confirmed that one of the identified peptides belongs to the family of crustacean hyperglycemic hormone, a peptide not previously observed in Spiralia. We propose that this discovery pipeline can be broadly applied to other systems in which one organism has evolved molecules to manipulate the physiology of another.

肽激素（peptide hormones）与神经肽（neuropeptides）是一类多样的生物活性分泌分子，可调控动物体内的关键生理过程。尽管肽类发现领域已取得诸多突破性成果，但仍有大量信号肽尚未被发掘。此前，我们团队利用芋螺（cone snails）中模拟生长抑素（somatostatin）的毒素，成功鉴定出生长抑素的无脊椎动物同源物（invertebrate ortholog）。本研究证实，这种基于毒素的研究方法可被系统性推广，用以发掘其他潜在具备信号功能的未知分泌肽（secretory peptides）。我们借助大规模测序数据集（sequencing datasets），搜索比对了芋螺毒素与该类蜗牛猎物分泌蛋白之间的同源性（homologies）。最终鉴定并验证了5个毒素家族的表达，它们与软体动物（mollusks）、环节动物（annelids）的未知分泌肽具有高度同源相似性，其中1个家族还与蜕皮动物（ecdysozoans）的未知分泌肽存在同源关系。基于多维度实验证据，我们提出此类肽类极有可能作为发挥关键生理功能的信号肽行使调控作用。实验证实，其中1种鉴定得到的肽类属于甲壳类高血糖激素（crustacean hyperglycemic hormone）家族——该类肽此前从未在螺旋动物（Spiralia）中被观测报道。我们认为，这套肽类发掘流程可被广泛推广应用于其他存在“某一生物演化出分子以调控另一生物生理机能”的研究体系中。