G-quadruplex DNA recognition by nucleophosmin: New insights from protein dissection

• Published in: Biochimica et biophysica acta Vol. 1840; no. 6; pp. 2050 - 2059
• Main Authors: Scognamiglio, Pasqualina Liana, Di Natale, Concetta, Leone, Marilisa, Poletto, Mattia, Vitagliano, Luigi, Tell, Gianluca, Marasco, Daniela
• Format: Journal Article
• Language: English
• Published: Netherlands 01.06.2014
• Subjects: Amino Acid Sequence; DNA; G-Quadruplexes; Humans; Magnetic Resonance Spectroscopy; Molecular Sequence Data; myeloid leukemia; Nuclear Proteins - chemistry; Nuclear Proteins - physiology; pathogenesis; peptides; Protein Folding; Proto-Oncogene Proteins c-myc - metabolism; Surface Plasmon Resonance; Helical stability; Disordered protein region
• ISSN: 0304-4165; 0006-3002
• DOI: 10.1016/j.bbagen.2014.02.017

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. 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. 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. 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. This study sheds new light in the molecular mechanism of the complex NPM1/G-quadruplex involved in acute myeloid leukemia (AML) disease.