G-quadruplex DNA recognition by nucleophosmin: new insights from protein dissection(577 views) Scognamiglio PL, Di Natale C, Leone M, Poletto M, Vitagliano L, Tell G, Marasco D
Keywords: Disordered Protein Region, Helical Stability, Surface Plasmon Resonance, Guanine Quadruplex, Myc Protein, Nucleophosmin, Article, Binding Affinity, Carboxy Terminal Sequence, Complex Formation, Controlled Study, Dna Binding, Priority Journal, Protein Motif, Protein Unfolding, Thermostability, Triple Helix, Circular Dichroism, Dna Helix, Molecular Recognition, Protein Determination, Protein Dissection, Protein Folding, Protein Protein Interaction, Protein Structure, Function And Variability, Structure Analysis, Amino Acid Sequence, G-Quadruplexes, Humans, Magnetic Resonance Spectroscopy, Molecular Sequence Data, Nuclear Proteins, Proto-Oncogene Proteins C-Myc, Nuclear Proteins Chemistry Physiology, Proto-Oncogene Proteins C-Myc Metabolism,
Affiliations: *** IBB - CNR ***
Department of Pharmacy, University of Naples Federico II, DFM-Scarl, 80134 Naples, Italy
CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, University of Naples Federico II, DFM-Scarl, 80134 Naples, Italy
Center for Advanced Biomaterials for Healthcare CRIB, Istituto Italiano di Tecnologia (IIT), 80125 Naples, Italy
Institute of Biostructures and Bioimaging, CNR, 80134 Naples, Italy
Department of Medical and Biological Sciences, University of Udine, 33100 Udine, Italy
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G-quadruplex DNA recognition by nucleophosmin: new insights from protein dissection
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.
G-quadruplex DNA recognition by nucleophosmin: new insights from protein dissection