Details

Autor(en) / Beteiligte

• Paoletti, Francesca
• Merzel, Franci
• Cassetta, Alberto
• Ogris, Iza
• Covaceuszach, Sonia
• Grdadolnik, Jože
• Lamba, Doriano
• Golič Grdadolnik, Simona

Titel

Endogenous modulators of neurotrophin signaling: Landscape of the transient ATP-NGF interactions

Ist Teil von

• Computational and structural biotechnology journal, 2021-01, Vol.19, p.2938-2949

Ort / Verlag

Elsevier B.V

Erscheinungsjahr

2021

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• [Display omitted] •High-resolution solution NMR structure of rhNGF has been determined.•Quinary interactions characterize ATP binding to rhNGF.•SPR, ITC and STD-NMR reveal ATP binding to rhNGF with mM affinity.•NMR and MD analysis pinpoint to the presence of two binding sites of ATP on rhNGF.•Stoichiometry of ATP-Mg2+ or Zn2+-rhNGF mixtures affects KD affinity to TrkA/p75NTR. The Nerve Growth Factor (NGF) neurotrophin acts in the maintenance and growth of neuronal populations. Despite the detailed knowledge of NGF’s role in neuron physiology, the structural and mechanistic determinants of NGF bioactivity modulated by essential endogenous ligands are still lacking. We present the results of an integrated structural and advanced computational approach to characterize the extracellular ATP-NGF interaction. We mapped by NMR the interacting surface and ATP orientation on NGF and revealed the functional role of this interaction in the binding to TrkA and p75NTR receptors by SPR. The role of divalent ions was explored in conjunction with ATP. Our results pinpoint ATP as a likely transient molecular modulator of NGF signaling, in health and disease states.