The N domain sequence in Ubr proteins was originally identified on the basis of its homology to learn more a small bacterial N recognin protein, ClpS. By incorporating the ClpS like N domain, Inhibitors,Modulators,Libraries canonical Ubr N recognins in eukaryotes acquired a specialized role for the recognition of N end residue in the Arg N end rule pathway and, simultaneously, a means to regulate peptide uptake. The binding region for type 1 residues is found within the eukaryote specific UBR domain that characterizes all Ubr proteins, including the non N recognins and the non canonical Ubr proteins. Previous stud ies have shown that the degradation of type 2 N end rule substrates is stimulated in the presence of type 1 dipeptides. Considering this, an unexpected observation in this study was that exogenous type 1 di peptides increased the amount of type 2 substrate.

In the case of TrpNd GFP, an increase was observed Inhibitors,Modulators,Libraries for at least two different type 1 dipeptides, Lys Leu and Arg Phe. In contrast, the type 2 dipeptide, Tyr Leu, did not affect the levels of ArgNd GFP, a type 1 substrate. Although the molecular mechanisms underlying this phenomenon need to be elucidated in future studies, the current data indicate that the recognition Inhibitors,Modulators,Libraries of type 2 substrates by N recognins is strongly influenced by the presence of type 1 dipeptides in a complex manner. Ubr ubiquitin ligases are necessary for protein quality control. In both S. cerevisiae and S. pombe, a mutation in the Ubr N recognin alleviates growth defects in several temperature sensitive mutants.

In this study, it was found that the ubr11 mutant was less sensitive to protein synthesis inhibitors than the wild type strains, suggesting that Ubr11 also contributes to quality control when partially defective proteins that retain some residual function are produced in the pres ence of low concentrations Inhibitors,Modulators,Libraries of protein synthesis inhibi tors. Alternatively, substrates of Ubr11 may be required for certain critical cellular processes that are more sen sitive to protein level alterations. In either case, inactiva tion of the Ubr11 dependent proteolysis of substrates alleviates growth inhibition. Interestingly, in S. cerevisiae, the quality control of several proteins is mediated by the Arg N end rule pathway, in which an unacetylated N terminal methionine is recognized by the type 2 amino acid binding site within Ubr1.

However, other studies have shown that the role of the Ubr proteins in quality control is independent of the N end rule pathway. Whether the Ubr proteins function as Inhibitors,Modulators,Libraries N recognins or act independently of the therefore N end rule pathway may depend on the substrate protein. As shown in this study, the ubr11 ClpS N domain mutant displayed altered responses to several drugs. Whether these defects involve recog nition of substrates with type 2 N end residues remains to be determined.