| The 26S proteasome is a highly abundant proteolytic complex involved in the degradation of ubiquitinated substrate proteins. It consists largely of two sub-complexes, the 20S catalytic core particle (CP) and the 19S/PA700 regulatory particle (RP) that can cap either end of the CP. The CP consists of two stacked heteroheptameric β-rings (β1-7) that contain three catalytic β-subunits and are flanked on either side by two heteroheptameric α-rings (α1-7). The RP includes a base and a lid, each having multiple subunits. The base, in part, is composed of a heterohexameric ring of ATPase subunits belonging to the AAA (ATPases Associated with diverse cellular Activities) family. The ATPase subunits function to unfold the substrate and open the gate formed by the α-subunits, thus exposing the unfolded substrate to the catalytic β-subunits. The lid consists of ubiquitin receptors and DUBs that function in recruitment of ubiquitinated substrates and modification of ubiquitin chain topology. Other modulators of proteasome activity, such as PA28/11S REG, can also bind to the end of the 20S CP and activate it. Of the subunits that comprise the 19S RP lid, only PSMD14 (POH1) has a known function. PSMD14 is classified as a metalloenzyme DUB and its activity has been shown to be critical for proteasome function in both yeast and humans. Indeed, PSMD14 harbors an Mpr1-Pad1-N-terminal (MPN) domain with an embedded, highly conserved signature motif for metal-dependent isopeptidases that has been dubbed JAMM, from Jab1/Pad1/MPN domain metalloenzyme. The JAMM motif of PSMD14 consists of a pattern of four charged amino acids: a glutamate residue followed by two histidines and an aspartate (EXnHXHX10D). It has been proposed that the histidine residues, in concert with the aspartate, bind to a zinc ion that, together with the preceding glutamate, forms the catalytic site of PSMD14. PSMD14 is thought to cleave ubiquitin chains with proximal specificity relative to the substrate, thus removing whole ubiquitin chains en bloc. Recent studies have implicated PSMD14 as an important regulator of ErbB2 and c-Jun protein levels. |
