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Secondary interaction between MDMX and p53 core domain inhibits p53 DNA binding
- Source :
- Proceedings of the National Academy of Sciences. 113
- Publication Year :
- 2016
- Publisher :
- Proceedings of the National Academy of Sciences, 2016.
-
Abstract
- The MDMX oncoprotein is an important regulator of tumor suppressor p53 activity during embryonic development. Despite sequence homology to the ubiquitin E3 ligase MDM2, MDMX depletion activates p53 without significant increase in p53 level, implicating a degradation-independent mechanism. We present evidence that MDMX inhibits the sequence-specific DNA binding activity of p53. This function requires the cooperation between MDMX and CK1α, and phosphorylation of S289 on MDMX. Depletion of MDMX or CK1α increases p53 DNA binding without stabilization of p53. A proteolytic fragment release assay revealed that in the MDMX-p53 complex, the MDMX acidic domain and RING domain interact stably with the p53 DNA binding domain. These interactions are referred to as secondary interactions because they only occur after the canonical-specific binding between the MDMX and p53 N termini, but exhibit significant binding stability in the mature complex. CK1α cooperates with MDMX to inhibit p53 DNA binding by further stabilizing the MDMX acidic domain and p53 core domain interaction. These results suggest that secondary intermolecular interaction is important in p53 regulation by MDMX, which may represent a common phenomenon in complexes containing multidomain proteins.
- Subjects :
- 0301 basic medicine
MDMX
Protein domain
Cell Cycle Proteins
Plasma protein binding
03 medical and health sciences
Protein Domains
Ubiquitin
Cell Line, Tumor
Neoplasms
Proto-Oncogene Proteins
Protein Interaction Mapping
Humans
Binding site
Binding Sites
Multidisciplinary
biology
Nuclear Proteins
DNA, Neoplasm
DNA-binding domain
Molecular biology
Cell biology
Ubiquitin ligase
030104 developmental biology
PNAS Plus
biology.protein
Mdm2
Tumor Suppressor Protein p53
Protein Binding
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 113
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....e84fd2f2d4bea1268d4286476c9d842a