Pasqualina Liana Scognamiglio1, Concetta Di Natale1, Marilisa Leone2, Mattia Poletto3, Luigi Vitagliano4, Gianluca Tell3, Daniela Marasco5. 1. Department of Pharmacy, 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. 2. Institute of Biostructures and Bioimaging, CNR, 80134 Naples, Italy; CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, University of Naples "Federico II", DFM-Scarl, 80134 Naples, Italy. 3. Department of Medical and Biological Sciences, University of Udine, 33100 Udine, Italy. 4. Institute of Biostructures and Bioimaging, CNR, 80134 Naples, Italy. 5. 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. Electronic address: daniela.marasco@unina.it.
Abstract
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.
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 humanmalignancies. 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.
Authors: Alessandro Arcovito; Sara Chiarella; Stefano Della Longa; Adele Di Matteo; Carlo Lo Sterzo; Giovanni Luca Scaglione; Luca Federici Journal: J Biol Chem Date: 2014-06-21 Impact factor: 5.157
Authors: Anna Russo; Pasqualina Liana Scognamiglio; Rolando Pablo Hong Enriquez; Carlo Santambrogio; Rita Grandori; Daniela Marasco; Antonio Giordano; Giacinto Scoles; Sara Fortuna Journal: PLoS One Date: 2015-08-07 Impact factor: 3.240
Authors: Anna Russo; Sara La Manna; Ettore Novellino; Anna Maria Malfitano; Daniela Marasco Journal: Asian J Androl Date: 2016 Sep-Oct Impact factor: 3.285