The conserved CPH domains of Cul7 and PARC are protein-protein interaction modules that bind the tetramerization domain of p53.
Cul7 is a member of the Cullin Ring Ligase (CRL) family and is required for normal mouse development and cellular proliferation. Recently, a region of Cul7 that is highly conserved in the p53-associated, Parkin-like cytoplasmic protein PARC, was shown to bind p53 directly. Here we identify the CPH domains (conserved domain within Cul7, PARC, and HERC2 proteins) of both Cul7 and PARC as p53 interaction domains using size exclusion chromatography and NMR spectroscopy. We present the first structure of the evolutionarily conserved CPH domain and provide novel insight into the Cul7-p53 interaction. The NMR structure of the Cul7-CPH domain reveals a fold similar to peptide interaction modules such as the SH3, Tudor, and KOW domains. The p53 interaction surface of both Cul7 and PARC CPH domains was mapped to a conserved surface distinct from the analogous peptide-binding regions of SH3, KOW, and Tudor domains, suggesting a novel mode of interaction. The CPH domain interaction surface of p53 resides in the tetramerization domain and is formed by residues contributed by at least two subunits.
Kaustov
Lilia
L
Ontario Cancer Institute and the Department of Medical Biophysics, University of Toronto, Ontario, Canada.
Lukin
Jonathan
J
Lemak
Alexander
A
Duan
Shili
S
Ho
Melissa
M
Doherty
Ryan
R
Penn
Linda Z
LZ
Arrowsmith
Cheryl H
CH
D020816:Amino Acid Motifs; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D017124:Conserved Sequence; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D014166:Transferases; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C506299:CUL7 protein, human; D002352:Carrier Proteins; D044842:Cullin Proteins; D016159:Tumor Suppressor Protein p53; C400192:Cul9 protein, human; D014166:Transferases