High resolution structure of a 6 MDa protease by xray-crystallography and cryo-EM

Cytosolic protein degradation proceeds largely via large protein complexes in which the active sites are located in secluded compartments. The paradigm for such a complex is the 26S proteasome, which degrades ubiquitinated proteins in an ATP-dependent manner. In the successive degradation of the resulting, relatively small products large complexes are also involved. Among them is Tripeptidyl Peptidase II (TPPII), a eukaryotic serine protease with a subtilisin-like active site, which acts mainly as an exopeptidase cleaving tripeptides from the free N-terminus of aminopeptides but also as an endopeptidase, albeit with a lower activity. Recently, TPPII has been attracting increasing attention owing to its extraordinary size, its apparent potential to substitute for some of the proteasome’s functions as well as its implication in MHC-class I peptide trimming, in neuropeptide degradation, in apoptosis, and in sepsis [1].