The guanylate kinase domain of the MAGUK PSD-95 binds dynamically to a conserved motif in MAP1a

Nat Struct Mol Biol. 2007 Feb;14(2):155-63. doi: 10.1038/nsmb1195. Epub 2007 Jan 14.


The postsynaptic density protein PSD-95 and related membrane-associated guanylate kinases are scaffolding proteins, whose modular interaction motifs organize protein complexes at cell junctions. The signature guanylate kinase domain (GK) contains elements of the protein's GMP-binding site but does not bind nucleotide. Instead, the GK domain has evolved from an enzyme to a protein-protein interaction motif. Here, we show that this canonical GMP-binding region interacts with microtubule-associated protein-1a (MAP1a) and we present a structural model. We determine the consensus GK-binding sequence in MAP1a and demonstrate that PSD-95 can use a similar interaction mode to bind diverse protein partners. Furthermore, we show that PSD-95 GK has adopted the conformational flexibility of the ancestral enzyme to bind its varied ligands, which suggests a mechanism of regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Conserved Sequence
  • Disks Large Homolog 4 Protein
  • Glutathione Transferase / chemistry
  • Glutathione Transferase / genetics
  • Guanylate Kinases / chemistry*
  • Intracellular Signaling Peptides and Proteins / chemistry*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Membrane Proteins / chemistry*
  • Membrane Proteins / genetics
  • Microtubule-Associated Proteins / chemistry*
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Binding
  • Rats
  • Recombinant Fusion Proteins / chemistry
  • src Homology Domains


  • Disks Large Homolog 4 Protein
  • Dlg4 protein, rat
  • Intracellular Signaling Peptides and Proteins
  • Map1a protein, rat
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Recombinant Fusion Proteins
  • Glutathione Transferase
  • Guanylate Kinases