PDZ Domain of Neuronal Nitric Oxide Synthase Recognizes Novel C-Terminal Peptide Sequences

Nicole L. Strieker, Karen S. Christopherson, Byungdoo A. Yi, Peter J. Schatz, Ronald W. Raab, Glenn Dawes, Douglas E. Bassett, David S. Bredt, Min Li

Research output: Contribution to journalArticlepeer-review

212 Scopus citations


PDZ domains are multifunctional protein-interaction motifs that often bind to the C-terminus of protein targets. Nitric oxide (NO), an endogenous signaling molecule, plays critical roles in nervous, immune, and cardiovascular function. Although there are numerous physiological functions for neuron-derived NO, produced primarily by the neuronal NO synthase (nNOS), excess nNOS activity mediates brain injury in cerebral ischemia and in animal models of Parkinson’s disease. Subcellular localization of nNOS activity must therefore be tightly regulated. To determine ligands for the PDZ domain of nNOS, we screened 13 billion distinct peptides and found that the nNOS-PDZ domain binds tightly to peptides ending Asp-X-Val. This differs from the only known (ThiYSer)-X-Val consensus that interacts with PDZ domains from PSD-95. Preference for Asp at the -2 peptide position is mediated by Tyr-77 of nNOS. A Y77D78 to H77E78 substitution changes the binding specificity from Asp-X-Val to Thr-X-Val. Guided by the Asp-X-Val consensus, candidate nNOS interacting proteins have been identified including glutamate and melatonin receptors. Our results demonstrate that PDZ domains have distinct peptide binding specificity.

Original languageEnglish (US)
Pages (from-to)336-342
Number of pages7
JournalNature biotechnology
Issue number4
StatePublished - Apr 1997
Externally publishedYes


  • NO
  • Neurotoxicity
  • PDZ
  • Peptide display

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Applied Microbiology and Biotechnology
  • Molecular Medicine
  • Biomedical Engineering


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