Structure, Function and Evolution of a Giant Enzyme, Tripeptidyl-Peptidase II

Abstract

Tripeptidyl-peptidase II (TPP II) is a giant exopeptidase with an active site of the subtilisin-type. Its main function is to remove tripeptides from a free N-terminal end of longer peptides. TPP II is active at neutral pH and is dependent on the same catalytic triad as other subtilases, i.e. Asp-44, His-264 and Ser-449 (numbering for murine TPP II). Furthermore, Glu-331 has been shown to be important for binding the N-terminal amino group of the substrate. Besides its exopeptidase activity, TPP II also appears to have a low endopeptidase activity. The large subunit (138 kDa in humans) forms a >4 MDa. Oligomerisation is essential for full enzymatic activity. The recently determined hybrid structure of the TPP II spindle from Drosophila melanogaster demonstrated that the active site is localized inside the spindle and that it is a self-compartmentalizing enzyme. TPP II is present in most eukaryotes, but has not been detected in archea and the homologous genes that appear in prokaryotes are suggested to be the result of a horizontal gene transfer. A role for TPP II in degradation of the neuropeptide cholecystokinin has been suggested, and the enzyme appears to be involved in trimming of some substrates for antigen presentation. However, considering its widespread distribution, this is probably not its main physiological function. A more reasonable assumption is that the enzyme has evolved to participate in a general protein turnover in the cytosol of most cells, presumably together with the proteasome and other peptidases.