Although many proteins have been found to exist as homooligomers in nature, the biological significance and mechanism for its occurring is far from clear. We have examined a variety
The atypical PKC isoforms （ζ and t） play essential roles in regulating various cellular processes. Both the hetero-interaction between PKCζand p62 through their N-terminal PB 1 domains and the homo-oligomerization...The atypical PKC isoforms （ζ and t） play essential roles in regulating various cellular processes. Both the hetero-interaction between PKCζand p62 through their N-terminal PB 1 domains and the homo-oligomerization of p62 via its PB 1 domain are critical for the activation of NF-r.B signaling; however, the molecular mechanisms concerning the formation and regulation of these homotypic complexes remain unclear. Here we determined the crystal structure of PKCζ-PB 1 in complex with a mono- meric p62-PB 1 mutant, where the massive electrostatic interactions between the acidic OPCA motif of PKCζ-PB 1 and the basic surface of p62-PB 1, as well as additional hydrogen bonds, ensure the formation of a stable and specific complex. The PKCζ-p62 interaction is interfered with the modification of a specific Cys of PKCζ by the antiarthritis drug aurothiomalate, though all four cysteine residues in the PKCζ-PB 1 domain can be modified in in vitro assay. In addition, detailed structural and biochemical analyses demonstrate that the PB 1 domains of aPKCs belong to the type I group, which can depolymerize the high-molecular-weight p62 aggregates into homo-oligomers of lower order. These data together unravel the molecular mecha- nisms of the homo- or hetero-interactions between p62 and PKCζ and provide the basis for designing inhibitors of NF-r,.B sig- naling.展开更多
文摘Although many proteins have been found to exist as homooligomers in nature, the biological significance and mechanism for its occurring is far from clear. We have examined a variety
基金supported in part by the National Natural Science Foundation of China(31070643 and 31130062)Tsinghua University(20121080028)
文摘The atypical PKC isoforms （ζ and t） play essential roles in regulating various cellular processes. Both the hetero-interaction between PKCζand p62 through their N-terminal PB 1 domains and the homo-oligomerization of p62 via its PB 1 domain are critical for the activation of NF-r.B signaling; however, the molecular mechanisms concerning the formation and regulation of these homotypic complexes remain unclear. Here we determined the crystal structure of PKCζ-PB 1 in complex with a mono- meric p62-PB 1 mutant, where the massive electrostatic interactions between the acidic OPCA motif of PKCζ-PB 1 and the basic surface of p62-PB 1, as well as additional hydrogen bonds, ensure the formation of a stable and specific complex. The PKCζ-p62 interaction is interfered with the modification of a specific Cys of PKCζ by the antiarthritis drug aurothiomalate, though all four cysteine residues in the PKCζ-PB 1 domain can be modified in in vitro assay. In addition, detailed structural and biochemical analyses demonstrate that the PB 1 domains of aPKCs belong to the type I group, which can depolymerize the high-molecular-weight p62 aggregates into homo-oligomers of lower order. These data together unravel the molecular mecha- nisms of the homo- or hetero-interactions between p62 and PKCζ and provide the basis for designing inhibitors of NF-r,.B sig- naling.
