Eckhart Leopold, Sachslehner Attila Placido, Steinbinder Julia, Fischer Heinz
Department of Dermatology, Medical University of Vienna, 1090, Vienna, Austria.
Division of Cell and Developmental Biology, Center for Anatomy and Cell Biology, Medical University of Vienna, 1090, Vienna, Austria.
J Mol Evol. 2025 May 20. doi: 10.1007/s00239-025-10252-w.
Caspases are cysteine-dependent aspartate-directed proteases which have critical functions in programmed cell death and inflammation. Their catalytic activity depends on a catalytic dyad of cysteine and histidine within a characteristic protein fold, the so-called caspase domain. Here, we investigated the evolution of caspase-16 (CASP16), an enigmatic member of the caspase family, for which only a partial human gene had been reported previously. The presence of CASP16 orthologs in placental mammals, marsupials and monotremes suggests that caspase-16 originated prior to the divergence of the main phylogenetic clades of mammals. Caspase-16 proteins of various species contain a carboxy-terminal caspase domain and an amino-terminal prodomain predicted to fold into a caspase domain-like structure, which is a unique feature among caspases known so far. Comparative sequence analysis indicates that the prodomain of caspase-16 has evolved by the duplication of exons encoding the caspase domain, whereby the catalytic site was lost in the amino-terminal domain and conserved in the carboxy-terminal domain of caspase-16. The murine and human orthologs of CASP16 contain frameshift mutations and therefore represent pseudogenes (CASP16P). CASP16 of the chimpanzee displays more than 98% nucleotide sequence identity with the human CASP16P gene but, like CASP16 genes of other primates, has an intact protein coding sequence. We conclude that caspase-16 structurally differs from other mammalian caspases, and the pseudogenization of CASP16 distinguishes humans from their phylogenetically closest relatives.
半胱天冬酶是一类依赖半胱氨酸的天冬氨酸定向蛋白酶，在程序性细胞死亡和炎症中发挥关键作用。它们的催化活性取决于一个由半胱氨酸和组氨酸组成的催化二元体，该二元体位于一个特征性的蛋白质折叠结构内，即所谓的半胱天冬酶结构域。在此，我们研究了半胱天冬酶家族中一个神秘成员——半胱天冬酶-16（CASP16）的进化情况，此前仅报道过其部分人类基因。胎盘哺乳动物、有袋类动物和单孔目动物中存在CASP16直系同源物，这表明半胱天冬酶-16起源于哺乳动物主要系统发育分支分化之前。不同物种的半胱天冬酶-16蛋白含有一个羧基末端半胱天冬酶结构域和一个氨基末端前结构域，该前结构域预计会折叠成类似半胱天冬酶结构域的结构，这是迄今为止已知的半胱天冬酶中的独特特征。比较序列分析表明，半胱天冬酶-16的前结构域是通过编码半胱天冬酶结构域的外显子重复进化而来的，由此催化位点在半胱天冬酶-16的氨基末端结构域中丢失，而在羧基末端结构域中得以保留。CASP16的小鼠和人类直系同源物含有移码突变，因此代表假基因（CASP16P）。黑猩猩的CASP16与人类CASP16P基因的核苷酸序列同一性超过98%，但与其他灵长类动物的CASP16基因一样，具有完整的蛋白质编码序列。我们得出结论，半胱天冬酶-16在结构上与其他哺乳动物半胱天冬酶不同，并且CASP16的假基因化使人类与其系统发育上最亲近的亲属区分开来。
