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Selectivity and promiscuity of the first and second PDZ domains of PSD-95 and synapse-associated protein 102.

PDZ domains typically interact with the very carboxyl terminus of their binding partners. Type 1 PDZ domains usually require valine, leucine, or isoleucine at the very COOH-terminal (P(0)) position, and serine or threonine 2 residues upstream at P(-2). We quantitatively defined the contributions of carboxyl-terminal residues to binding selectivity of the prototypic interactions of the PDZ domains of postsynaptic density protein 95 (PSD-95) and its homolog synapse-associated protein 90 (SAP102) with the NR2b subunit of the N-methyl-d-aspartate-type glutamate receptor. Our studies indicate that all of the last five residues of NR2b contribute to the binding selectivity. Prominent were a requirement for glutamate or glutamine at P(-3) and for valine at P(0) for high affinity binding and a preference for threonine over serine at P(-2), in the context of the last 11 residues of the NR2b COOH terminus. This analysis predicts a COOH-terminal (E/Q)(S/T)XV consensus sequence for the strongest binding to the first two PDZ domains of PSD-95 and SAP102. A search of the human genome sequences for proteins with a COOH-terminal (E/Q)(S/T)XV motif yielded 50 proteins, many of which have not been previously identified as PSD-95 or SAP102 binding partners. Two of these proteins, brain-specific angiogenesis inhibitor 1 and protein kinase Calpha, co-immunoprecipitated with PSD-95 and SAP102 from rat brain extracts.

Pubmed ID: 11937501


  • Lim IA
  • Hall DD
  • Hell JW


The Journal of biological chemistry

Publication Data

June 14, 2002

Associated Grants

  • Agency: NIA NIH HHS, Id: AG00213
  • Agency: NIDDK NIH HHS, Id: DK07759
  • Agency: NINDS NIH HHS, Id: R01-NS35563

Mesh Terms

  • Amino Acid Sequence
  • Angiogenesis Inhibitors
  • Angiogenic Proteins
  • Animals
  • Anisotropy
  • Brain
  • Dose-Response Relationship, Drug
  • Frizzled Receptors
  • Genome, Human
  • Glutathione Transferase
  • Humans
  • Immunoblotting
  • Intracellular Signaling Peptides and Proteins
  • Isoenzymes
  • Kinetics
  • Membrane Proteins
  • Models, Molecular
  • Molecular Sequence Data
  • Nerve Tissue Proteins
  • Neuropeptides
  • Nuclear Proteins
  • Peptides
  • Precipitin Tests
  • Protein Binding
  • Protein Kinase C
  • Protein Kinase C-alpha
  • Protein Structure, Tertiary
  • Proteins
  • Rats
  • Receptors, G-Protein-Coupled
  • Receptors, Neurotransmitter
  • Recombinant Fusion Proteins
  • Sequence Homology, Amino Acid
  • Serine
  • Spectrometry, Fluorescence
  • Threonine
  • Transcription Factors