Phosphorylation of a PDZ domain extension modulates binding affinity and interdomain interactions in postsynaptic density-95 (PSD-95) protein, a membrane-associated guanylate kinase (MAGUK).

Academic Article

Abstract

  • Postsynaptic density-95 is a multidomain scaffolding protein that recruits glutamate receptors to postsynaptic sites and facilitates signal processing and connection to the cytoskeleton. It is the leading member of the membrane-associated guanylate kinase family of proteins, which are defined by the PSD-95/Discs large/ZO-1 (PDZ)-Src homology 3 (SH3)-guanylate kinase domain sequence. We used NMR to show that phosphorylation of conserved tyrosine 397, which occurs in vivo and is located in an atypical helical extension (α3), initiates a rapid equilibrium of docked and undocked conformations. Undocking reduced ligand binding affinity allosterically and weakened the interaction of PDZ3 with SH3 even though these domains are separated by a ~25-residue linker. Additional phosphorylation at two linker sites further disrupted the interaction, implicating α3 and the linker in tuning interdomain communication. These experiments revealed a novel mode of regulation by a detachable PDZ element and offer a first glimpse at the dynamic interaction of PDZ and SH3-guanylate kinase domains in membrane-associated guanylate kinases.
  • Published In

    Keywords

  • Allosteric Regulation, Disks Large Homolog 4 Protein, Guanylate Kinases, Humans, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Nuclear Magnetic Resonance, Biomolecular, PDZ Domains, Phosphorylation, Structure-Activity Relationship, src Homology Domains
  • Digital Object Identifier (doi)

    Author List

  • Zhang J; Petit CM; King DS; Lee AL
  • Start Page

  • 41776
  • End Page

  • 41785
  • Volume

  • 286
  • Issue

  • 48