Your browser doesn't support javascript.
loading
Unexpected Heterodivalent Recruitment of NOS1AP to nNOS Reveals Multiple Sites for Pharmacological Intervention in Neuronal Disease Models.
Li, Li-Li; Melero-Fernandez de Mera, Raquel M; Chen, Jia; Ba, Wei; Kasri, Nael Nadif; Zhang, Mingjie; Courtney, Michael J.
Afiliación
  • Li LL; Department of Neurobiology, A. I. Virtanen Institute, University of Eastern Finland, Kuopio, FIN 70210, Finland.
  • Melero-Fernandez de Mera RM; Department of Neurobiology, A. I. Virtanen Institute, University of Eastern Finland, Kuopio, FIN 70210, Finland.
  • Chen J; Division of Life Science, Center for Systems Biology and Human Health, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
  • Ba W; Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Department of Cognitive Neuroscience, Nijmegen 6500 HB, The Netherlands, and.
  • Kasri NN; Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Department of Cognitive Neuroscience, Nijmegen 6500 HB, The Netherlands, and.
  • Zhang M; Division of Life Science, Center for Systems Biology and Human Health, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
  • Courtney MJ; Department of Neurobiology, A. I. Virtanen Institute, University of Eastern Finland, Kuopio, FIN 70210, Finland, Turku Centre for Biotechnology, Åbo Akademi University and University of Turku, Turku, FIN 20521, Finland miccou@utu.fi.
J Neurosci ; 35(19): 7349-64, 2015 May 13.
Article en En | MEDLINE | ID: mdl-25972165
The protein NOS1AP/CAPON mediates signaling from a protein complex of NMDA receptor, PSD95 and nNOS. The only stroke trial for neuroprotectants that showed benefit to patients targeted this ternary complex. NOS1AP/nNOS interaction regulates small GTPases, iron transport, p38MAPK-linked excitotoxicity, and anxiety. Moreover, the nos1ap gene is linked to disorders from schizophrenia, post-traumatic stress disorder, and autism to cardiovascular disorders and breast cancer. Understanding protein interactions required for NOS1AP function, therefore, has broad implications for numerous diseases. Here we show that the interaction of NOS1AP with nNOS differs radically from the classical PDZ docking assumed to be responsible. The NOS1AP PDZ motif does not bind nNOS as measured by multiple methods. In contrast, full-length NOS1AP forms an unusually stable interaction with nNOS. We mapped the discrepancy between full-length and C-terminal PDZ motif to a novel internal region we call the ExF motif. The C-terminal PDZ motif, although neither sufficient nor necessary for binding, nevertheless promotes the stability of the complex. It therefore potentially affects signal transduction and suggests that functional interaction of nNOS with NOS1AP might be targetable at two distinct sites. We demonstrate that excitotoxic pathways can be regulated, in cortical neuron and organotypic hippocampal slice cultures from rat, either by the previously described PDZ ligand TAT-GESV or by the ExF motif-bearing region of NOS1AP, even when lacking the critical PDZ residues as long as the ExF motif is intact and not mutated. This previously unrecognized heterodivalent interaction of nNOS with NOS1AP may therefore provide distinct opportunities for pharmacological intervention in NOS1AP-dependent signaling and excitotoxicity.
Asunto(s)
Palabras clave

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Proteínas Adaptadoras Transductoras de Señales / Óxido Nítrico Sintasa de Tipo I / Neuronas Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: J Neurosci Año: 2015 Tipo del documento: Article País de afiliación: Finlandia

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Proteínas Adaptadoras Transductoras de Señales / Óxido Nítrico Sintasa de Tipo I / Neuronas Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: J Neurosci Año: 2015 Tipo del documento: Article País de afiliación: Finlandia