Journal
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
Volume 1840, Issue 6, Pages 2050-2059Publisher
ELSEVIER
DOI: 10.1016/j.bbagen.2014.02.017
Keywords
Disordered protein region; Surface Plasmon Resonance; Helical stability
Categories
Funding
- MIUR Ricerca e Competitivita [PON 01_2388]
- Italian Association for Cancer Research [IG14038]
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Background: Nucleophosmin (NPM1, B23) is a multifunctional protein that is involved in a variety of fundamental biological processes. NPM1/B23 deregulation is implicated in the pathogenesis of several human malignancies. This protein exerts its functions through the interaction with a multiplicity of biological partners. Very recently it is has been shown that NPM1/B23 specifically recognizes DNA G-quadruplexes through its C-terminal region. Methods: Through a rational dissection approach of protein here we show that the intrinsically unfolded regions of NPM1/B23 significantly contribute to the binding of c-MYC G-quadruplex motif. Interestingly, the analysis of the ability of distinct NPM1/B23 fragments to bind this quadruplex led to the identifications of distinct NPM1/ B23-based peptides that individually present a high affinity for this motif. Results: These results suggest that the tight binding of NPM1/B23 to the G-quadruplex is achieved through the cooperation of both folded and unfolded regions that are individually able to bind it. The dissection of NPM1/ B23 also unveils that its H1 helix is intrinsically endowed with an unusual thermal stability. Conclusions: These findings have implications for the unfolding mechanism of NPM1/B23, for the G-quadruplex affinity of the different NPM1/B23 isoforms and for the design of peptide-based molecules able to interact with this DNA motif. General observation: This study sheds new light in the molecular mechanism of the complex NPM1/G-quadruplex involved in acute myeloid leukemia (AML) disease. (c) 2014 Elsevier B.V. All rights reserved.
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