Capotosti Francesca, Hsieh James J-D, Herr Winship
Center for Integrative Genomics, University of Lausanne, Génopode Building, 1015 Lausanne, Switzerland.
Mol Cell Biol. 2007 Oct;27(20):7063-72. doi: 10.1128/MCB.00769-07. Epub 2007 Aug 13.
Site-specific proteolytic processing plays important roles in the regulation of cellular activities. The histone modification activity of the human trithorax group mixed-lineage leukemia (MLL) protein and the cell cycle regulatory activity of the cell proliferation factor herpes simplex virus host cell factor 1 (HCF-1) are stimulated by cleavage of precursors that generates stable heterodimeric complexes. MLL is processed by a protease called taspase 1, whereas the precise mechanisms of HCF-1 maturation are unclear, although they are known to depend on a series of sequence repeats called HCF-1(PRO) repeats. We demonstrate here that the Drosophila homologs of MLL and HCF-1, called Trithorax and dHCF, are both cleaved by Drosophila taspase 1. Although highly related, the human and Drosophila taspase 1 proteins display cognate species specificity. Thus, human taspase 1 preferentially cleaves MLL and Drosophila taspase 1 preferentially cleaves Trithorax, consistent with coevolution of taspase 1 and MLL/Trithorax proteins. HCF proteins display even greater species-specific divergence in processing: whereas dHCF is cleaved by the Drosophila taspase 1, human and mouse HCF-1 maturation is taspase 1 independent. Instead, human and Xenopus HCF-1PRO repeats are cleaved in vitro by a human proteolytic activity with novel properties. Thus, from insects to humans, HCF proteins have conserved proteolytic maturation but evolved different mechanisms.
位点特异性蛋白水解加工在细胞活动的调节中发挥着重要作用。人类三胸复合物混合谱系白血病（MLL）蛋白的组蛋白修饰活性以及细胞增殖因子单纯疱疹病毒宿主细胞因子1（HCF-1）的细胞周期调节活性，会因前体的切割而受到刺激，这种切割会产生稳定的异二聚体复合物。MLL由一种名为taspase 1的蛋白酶进行加工，而HCF-1成熟的精确机制尚不清楚，尽管已知其依赖于一系列称为HCF-1（PRO）重复序列。我们在此证明，MLL和HCF-1在果蝇中的同源物，即三胸复合物（Trithorax）和果蝇HCF（dHCF），都被果蝇taspase 1切割。尽管人类和果蝇的taspase 1蛋白高度相关，但它们表现出同源物种特异性。因此，人类taspase 1优先切割MLL，果蝇taspase 1优先切割三胸复合物，这与taspase 1和MLL/三胸复合物蛋白的共同进化一致。HCF蛋白在加工过程中表现出更大的物种特异性差异：dHCF被果蝇taspase 1切割，而人类和小鼠的HCF-1成熟不依赖于taspase 1。相反，人类和非洲爪蟾的HCF-1 PRO重复序列在体外被一种具有新特性的人类蛋白水解活性切割。因此，从昆虫到人类，HCF蛋白具有保守的蛋白水解成熟过程，但进化出了不同的机制。
