Granulins are a family of unique protein growth factors which are found in a range of species and have several bioactivities that include cell proliferation and wound healing. They typically contain six disulfide bonds, but the sequences, structures and bioactivities vary significantly. We have previously shown that an N-terminally truncated version of a granulin from the human liver fluke, Opisthorchis viverrini, can fold independently into a “mini-granulin” structure and has potent wound healing properties in vivo. The incorporation of a non-native third disulfide bond, with respect to the full-length granulin module, was critical for the formation of regular secondary structure in the liver fluke derived peptide. By contrast, this third disulfide bond is not required for a carp granulin-1 truncated peptide to fold independently. This distinction led us to explore granulins from the zebrafish model organism. Here we show that the mini-granulin fold occurs in a naturally occurring paragranulin (half-domain) from zebrafish, and is also present in a truncated form of a full-length zebrafish granulin, suggesting this structure might be a common property in either naturally occurring or engineered N-terminally truncated granulins and the carp granulin-1 folding is an anomaly. The in vitro folding yield is significantly higher in the naturally occurring paragranulin, but only the truncated zebrafish granulin peptide promoted the proliferation of fibroblasts consistent with a growth factor function, and therefore the function of the paragranulin remains unknown. These findings provide insight into the folding and evolution of granulin domains and might be useful in the elucidation of the structural features important for bioactivity to aid the design of more potent and stable analogues for the development of novel wound healing agents.

中文翻译：

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截短的颗粒蛋白肽的折叠。

颗粒蛋白是在一系列物种中发现的独特蛋白质生长因子家族，具有多种生物活性，包括细胞增殖和伤口愈合。它们通常含有六个二硫键，但序列，结构和生物活性差异很大。先前我们已经表明，人肝吸虫Opisthorchis viverrini的颗粒蛋白的N末端截短形式可以独立折叠成“小颗粒”结构，并在体内具有有效的伤口愈合特性。相对于全长颗粒蛋白模块，非天然的第三二硫键的结合对于在肝吸虫衍生的肽中形成规则的二级结构至关重要。相比之下，鲤鱼颗粒1截短肽独立折叠不需要该第三二硫键。这种区别使我们探索了斑马鱼模型生物中的颗粒蛋白。在这里，我们显示了迷你颗粒蛋白折叠出现在自然产生的斑马鱼副颗粒蛋白（半结构域）中，并且也以全长斑马鱼颗粒蛋白的截短形式存在，提示这种结构可能是天然存在的或经工程改造的N末端截短的颗粒蛋白的共同属性，而鲤鱼颗粒1折叠是异常现象。在天然存在的副颗粒蛋白中，体外折叠产率显着更高，但是只有截短的斑马鱼颗粒蛋白肽才促进成纤维细胞的增殖，这与生长因子功能一致，因此，副颗粒蛋白的功能仍然未知。这些发现提供了对颗粒蛋白结构域的折叠和进化的见解，并且对于阐明对生物活性重要的结构特征可能是有用的，以帮助设计更有效和稳定的类似物以开发新型伤口愈合剂。但是只有截短的斑马鱼颗粒蛋白肽能促进成纤维细胞的增殖，并具有生长因子的功能，因此副颗粒蛋白的功能仍然未知。这些发现提供了对颗粒蛋白结构域的折叠和进化的见解，并且对于阐明对于生物活性重要的结构特征可能是有用的，以帮助设计更有效和稳定的类似物以开发新型伤口愈合剂。但是只有截短的斑马鱼颗粒蛋白肽能促进成纤维细胞的增殖，并具有生长因子的功能，因此副颗粒蛋白的功能仍然未知。这些发现提供了对颗粒蛋白结构域的折叠和进化的见解，并且对于阐明对于生物活性重要的结构特征可能是有用的，以帮助设计更有效和稳定的类似物以开发新型伤口愈合剂。