Abstract:
:The negative regulatory domain (NRD) of the p53 tumor suppressor is intrinsically disordered. It contains several posttranslational modification (PTM) sites that are important for regulation of p53 activity. Calcium-dependent binding of dimeric S100B(ββ) to p53-NRD blocks access to these PTM sites and disrupts the p53 tetramer to inhibit p53 activation. Previous nuclear magnetic resonance (NMR) structural studies have suggested that p53-NRD folds into a stable helix upon binding to S100B(ββ). Intriguingly, despite the well-converged and stably folded nature of the NMR structure ensemble, experimentally resolved intermolecular nuclear Overhauser enhancements (NOEs) are extremely weak; most have 5- to 6-Å upper bounds, and mainly involve the C-terminal segment of p53-NRD. Such a systematic lack of strong intermolecular NOEs could suggest that the p53/S100B(ββ) interface is more dynamic than currently believed. Indeed, extensive atomistic simulations in explicit solvent (with 1.0μs total effective sampling) revealed large heterogeneity in the S100B(ββ)-bound conformation of p53-NRD. Helix unwinding at the C-terminus allows key hydrophobic residues (Leu383 and Phe385) to make more extensive intermolecular contacts, whereas the highly helical N-terminus displays substantial flexibility in packing with S100B(ββ). Importantly, the predicted heterogeneous ensemble as a whole is highly consistent with experimental intermolecular NOEs, although many conformational sub-states coexist and individual sub-states satisfy only subsets of the NOE restraints. Furthermore, the simulated ensemble provides similar shielding of key PTM sites to support p53 inhibition. This study not only provides new insights into the structural basis of the p53/S100B(ββ) recognition but also highlights the importance of recognizing dynamic complexes in structural studies of intrinsically disordered protein interactions.
journal_name
J Mol Bioljournal_title
Journal of molecular biologyauthors
McDowell C,Chen J,Chen Jdoi
10.1016/j.jmb.2013.01.001subject
Has Abstractpub_date
2013-03-25 00:00:00pages
999-1010issue
6eissn
0022-2836issn
1089-8638pii
S0022-2836(13)00004-1journal_volume
425pub_type
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