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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 RIS Download

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

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Associated grants

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

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