title: Cross-talk between prion protein and quadruplex-forming nucleic acids: a dynamic complex formation.
abstract: Prion protein (PrP) is involved in lethal neurodegenerative diseases, and many issues remain unclear about its physio-pathological role. Quadruplex-forming nucleic acids (NAs) have been found to specifically bind to both PrP cellular and pathological isoforms. To clarify the relevance of these interactions, thermodynamic, kinetic and structural studies have been performed, using isothermal titration calorimetry, surface plasmon resonance and circular dichroism methodologies. Three quadruplex-forming sequences, d(TGGGGT), r(GGAGGAGGAGGA), d(GGAGGAGGAGGA), and various forms of PrP were selected for this study. Our results showed that these quadruplexes exhibit a high affinity and specificity toward PrP, with K(D) values within the range 62÷630 nM, and a weaker affinity toward a PrP-β oligomer, which mimics the pathological isoform. We demonstrated that the NA quadruplex architecture is the structural determinant for the recognition by both PrP isoforms. Furthermore, we spotted both PrP N-terminal and C-terminal domains as the binding regions involved in the interaction with DNA/RNAs, using several PrP truncated forms. Interestingly, a reciprocally induced structure loss was observed upon PrP-NA interaction. Our results allowed to surmise a quadruplex unwinding-activity of PrP, that may have a feedback in vivo.
authors.affiliation: Dipartimento delle Scienze Biologiche, Università degli Studi di Napoli Federico II, Naples 80134, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Cavaliere
authors.forename: Bruno
authors.initials: B
authors.lastname: Pagano
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Granata
authors.forename: Stephanie
authors.initials: S
authors.lastname: Prigent
authors.forename: Human
authors.initials: H
authors.lastname: Rezaei
authors.forename: Concetta
authors.initials: C
authors.lastname: Giancola
authors.forename: Adriana
authors.initials: A
authors.lastname: Zagari
mesh_terms: D001665:Binding Sites; D002151:Calorimetry; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry; D054856:G-Quadruplexes; D007700:Kinetics; D011328:Prions / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D012313:RNA / Q000737:chemistry; D020349:Surface Plasmon Resonance; D013816:Thermodynamics
chemical_list: D011328:Prions; D012313:RNA; D004247:DNA