PROSITE documentation PDOC52081

CPH (CUL7, PARC, and HERC2) domain profile

The p53 tumor suppressor responds to cellular stress by inducing apoptosis, senescence, and growth arrest. Regulation of stress responses by p53 is primarily mediated through its action as a transcription factor. The predominant mechanisms controlling p53 function are regulation of its protein stability, subcellular localization, and post-translational modification. Ubiquitin-mediated proteasomal targeting of p53 serves to regulate p53 protein levels. The tetramerization domain (TD) of p53 has been implicated in multiple aspects of p53 function including sequence-specific DNA binding, subcellular localization, and protein-protein interactions [1,2,3,4,5].

Ubiquitination involves a cascade of enzymes beginning with activation of ubiquitin by the E1 ubiquitin-activating enzyme. Following activation, ubiquitin is transferred first to an E2 ubiquitin conjugating enzyme and then to an E3 ubiquitin ligase. E3 ligases serve to recruit specific substrates for subsequent poly-ubiquitination. E3 ubiquitin ligases have been classified into two main types: HECT and RING [1,2,3,4,5].

The RING E3 ubiquitin ligases Cullin 7 (CUL7) and Parkin-like cytoplasmic (PARC, also known as Cullin 9), and the HECT E3 ubiquitin ligase HECT- and RCC1-like domains 2 (HERC2) contain a common domain named CPH (a conserved domain within Cul7, PARC, and HERC2 proteins). CPH domains are protein-protein interaction modules that bind the TD of p53. Proteins with a CPH domain bind p53 and regulate its activity in different ways. Thus, whereas CUL7 and PARC promote cell growth by antagonizing p53 functions, HERC2 activates p53, thus inhibiting cell cycle progression [1,2,3,4,5].

The CPH domain has a β-barrel architecture consisting of five antiparallel β-strands, three loops, and an α-helix. Strands β1-β2 are connected by a long turn, β2-β3 and β3-β4 are connected by a short turn, whereas strands β4 and β5 are linked by a helical turn (see <PDB:2JNG>). The arrangement of β sheets in the CPH domain is almost identical to that found in SH3, Tudor, and KOW domains. Nevertheless, there is significant variability in the length and arrangement of the loops that contribute to peptide binding in each domain. Furthermore, despite the similar fold, all three domains display variety in the location of functional binding sites. Thus, each module uses the same fold in a unique manner to interact with partners [3].

The profile we developed covers the entire CPH domain.