Journal article
Modeling the accessible conformations of the intrinsically unstructured transactivation domain of p53
Proteins, structure, function, and bioinformatics, Vol.71(2), pp.587-598
05/01/2008
Handle:
https://hdl.handle.net/2376/113397
PMID: 17972286
Abstract
Internuclear distances derived from paramagnetic relaxation enhancement (PRE) data were used to restrain molecular dynamics simulations of the intrinsically unstructured transactivation domain of the tumor suppressor protein, p53. About 1000 structures were simulated using ensemble averaging of replicate molecules to compensate for the inherent bias in the PRE-derived distances. Gyration radii measurements on these structures show that the p53 transactivation domain (p53TAD) is statistically predominantly in a partially collapsed state that is unlike the open structure that is found for p53TAD bound to either the E3 ubiquitin ligase, MDM2, or the 70 kDa subunit of replication protein A, RPA70. Contact regions that potentially mediate the collapse were identified and found to consist of mostly hydrophobic residues. The identified contact regions preferentially place the MDM2 and RPA70 binding regions in close proximity. We show that our simulations thoroughly sample the available range of conformations and that a fraction of the molecules are in an open state that would be competent for binding either MDM2 or RPA70. We also show that the Stokes radius estimated from the average gyration radius of the ensemble is in good agreement with the value determined using size exclusion chromatography. Finally, the presence of a persistent loop localized to a PXP motif was identified. Serine residues flanking the PXP motif become phosphorylated in response to DNA damage, and we postulate that this will perturb the equilibrium population to more open conformations.
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Details
- Title
- Modeling the accessible conformations of the intrinsically unstructured transactivation domain of p53
- Creators
- David F Lowry - Department of Microbiology, Molecular Biology, and Biochemistry, University of Idaho, Life Science South Rm. 140, Moscow, Idaho 83844-3052, USAAmber StancikRanjay Mann ShresthaGary W Daughdrill
- Publication Details
- Proteins, structure, function, and bioinformatics, Vol.71(2), pp.587-598
- Academic Unit
- Engineering and Applied Sciences (TRIC), School of
- Publisher
- United States
- Grant note
- P20 RR 16448 / NCRR NIH HHS P20 RR 16454-02 / NCRR NIH HHS
- Identifiers
- 99900548197601842
- Language
- English
- Resource Type
- Journal article