Hsieh James J-D, Cheng Emily H-Y, Korsmeyer Stanley J
Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Cell. 2003 Oct 31;115(3):293-303. doi: 10.1016/s0092-8674(03)00816-x.
The Mixed-Lineage Leukemia gene (MLL/HRX/ALL1) encodes a large nuclear protein homologous to Drosophila trithorax that is required for the maintenance of HOX gene expression. MLL is cleaved at two conserved sites generating N320 and C180 fragments, which heterodimerize to stabilize the complex and confer its subnuclear destination. Here, we purify and clone the protease responsible for cleaving MLL. We entitle it Taspase1 as it initiates a class of endopeptidases that utilize an N-terminal threonine as the active site nucleophile to proteolyze polypeptide substrates following aspartate. Taspase1 proenzyme is intramolecularly proteolyzed generating an active 28 kDa alpha/22 kDa beta heterodimer. RNAi-mediated knockdown of Taspase1 results in the appearance of unprocessed MLL and the loss of proper HOX gene expression. Taspase1 coevolved with MLL/trithorax as Arthropoda and Chordata emerged from Metazoa suggesting that Taspase1 originated to regulate complex segmental body plans in higher organisms.
混合谱系白血病基因（MLL/HRX/ALL1）编码一种与果蝇三胸蛋白同源的大型核蛋白，该蛋白是维持HOX基因表达所必需的。MLL在两个保守位点被切割，产生N320和C180片段，这两个片段异源二聚化以稳定复合物并确定其亚核定位。在这里，我们纯化并克隆了负责切割MLL的蛋白酶。我们将其命名为Taspase1，因为它启动了一类内肽酶，这类内肽酶利用N端苏氨酸作为活性位点亲核试剂，在天冬氨酸之后对多肽底物进行蛋白水解。Taspase1酶原在分子内被蛋白水解，产生一个有活性的28 kDaα/22 kDaβ异源二聚体。RNA干扰介导的Taspase1敲低导致未加工的MLL出现以及HOX基因正常表达的丧失。随着节肢动物和脊索动物从后生动物中分化出来，Taspase1与MLL/三胸蛋白共同进化，这表明Taspase1起源于调控高等生物复杂的体节模式。
