Synergic Role of Nucleophosmin Three-helix Bundle and a Flanking Unstructured Tail in the Interaction with G-quadruplex DNA

Alessandro Arcovito, Sara Chiarella, Stefano Della Longa, Adele Di Matteo, Carlo Lo Sterzo, Giovanni Luca Scaglione, Luca Federici

Risultato della ricerca: Contributo in rivistaArticolo in rivista

14 Citazioni (Scopus)


Nucleophosmin (NPM1) is a nucleocytoplasmic shuttling protein, mainly localized at nucleoli, that plays a number of functions in ribosome biogenesis and export, cell cycle control, and response to stress stimuli. NPM1 is the most frequently mutated gene in acute myeloid leukemia; mutations map to the C-terminal domain of the protein and cause its denaturation and aberrant cytoplasmic translocation. NPM1 C-terminal domain binds G-quadruplex regions at ribosomal DNA and at gene promoters, including the well characterized sequence from the nuclease-hypersensitive element III region of the c-MYC promoter. These activities are lost by the leukemic variant. Here we analyze the NPM1/G-quadruplex interaction, focusing on residues belonging to both the NPM1 terminal three-helix bundle and a lysine-rich unstructured tail, which has been shown to be necessary for high affinity recognition. We performed extended site-directed mutagenesis and measured binding rate constants through surface plasmon resonance analysis. These data, supported by molecular dynamics simulations, suggest that the unstructured tail plays a double role in the reaction mechanism. On the one hand, it facilitates the formation of an encounter complex through long range electrostatic interactions; on the other hand, it directly contacts the G-quadruplex scaffold through multiple and transient electrostatic interactions, significantly enlarging the contact surface.
Lingua originaleEnglish
pagine (da-a)21230-21241
Numero di pagine12
RivistaJournal of Biological Chemistry
Stato di pubblicazionePubblicato - 2014


  • Encounter Complex
  • Flanking Fuzziness
  • Intrinsically Disordered Protein
  • Leukemia
  • Molecular Dynamics
  • Protein-DNA Interaction
  • Surface Plasmon Resonance (SPR)


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