Species selectivity of mixed-lineage leukemia/trithorax and HCF proteolytic maturation pathways

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism
  • Endopeptidases / genetics
  • Endopeptidases / metabolism*
  • Enzyme Stability
  • Evolution, Molecular
  • HeLa Cells
  • Humans
  • Mice
  • Molecular Sequence Data
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • Myeloid-Lymphoid Leukemia Protein / metabolism*
  • Protease Inhibitors / metabolism
  • Protein Precursors / genetics
  • Protein Precursors / metabolism*
  • RNA Interference
  • Sequence Alignment
  • Substrate Specificity


  • Chromosomal Proteins, Non-Histone
  • Drosophila Proteins
  • Protease Inhibitors
  • Protein Precursors
  • host cell factor, Drosophila
  • trx protein, Drosophila
  • Myeloid-Lymphoid Leukemia Protein
  • Endopeptidases
  • taspase1, Drosophila
  • taspase1, human