{PDOC52081}
{PS52081; CPH}
{BEGIN}
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* CPH (CUL7, PARC, and HERC2) domain profile *
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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 beta-barrel architecture consisting of five antiparallel
beta-strands, three   loops,  and  an  alpha-helix.  Strands  beta1-beta2  are
connected by a long turn, beta2-beta3 and beta3-beta4 are connected by a short
turn, whereas  strands  beta4  and  beta5  are  linked  by a helical turn (see
<PDB:2JNG>). The  arrangement  of  beta  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.

-Sequences known to belong to this class detected by the profile: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.
-Last update: November 2025 / First entry.

[ 1] Kasper J.S., Arai T., DeCaprio J.A.
     "A novel p53-binding domain in CUL7."
     Biochem. Biophys. Res. Commun. 348:132-138(2006).
     PubMed=16875676; DOI=10.1016/j.bbrc.2006.07.013
[ 2] Andrews P., He Y.J., Xiong Y.
     "Cytoplasmic localized ubiquitin ligase cullin 7 binds to p53 and
     promotes cell  growth by antagonizing p53 function."
     Oncogene 25:4534-4548(2006).
     PubMed=16547496; DOI=10.1038/sj.onc.1209490
[ 3] Kaustov L., Lukin J., Lemak A., Duan S., Ho M., Doherty R., Penn L.Z.,
     Arrowsmith C.H.
     "The conserved CPH domains of Cul7 and PARC are protein-protein
     interaction  modules that bind the tetramerization domain of p53."
     J. Biol. Chem. 282:11300-11307(2007).
     PubMed=17298945; DOI=10.1074/jbc.M611297200
[ 4] Cubillos-Rojas M., Amair-Pinedo F., Peiro-Jordan R., Bartrons R.,
     Ventura F., Rosa J.L.
     "The E3 ubiquitin protein ligase HERC2 modulates the activity of tumor
     protein p53  by regulating its oligomerization."
     J. Biol. Chem. 289:14782-14795(2014).
     PubMed=24722987; DOI=10.1074/jbc.M113.527978
[ 5] Garcia-Cano J., Sanchez-Tena S., Sala-Gaston J., Figueras A.,
     Vinals F., Bartrons R., Ventura F., Rosa J.L.
     "Regulation of the MDM2-p53 pathway by the ubiquitin ligase HERC2."
     Mol. Oncol. 14:69-86(2020).
     PubMed=31665549; DOI=10.1002/1878-0261.12592

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