David S King

Publications (2)9.55 Total impact

• Article: 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).

  Jun Zhang, Chad M Petit, David S King, Andrew L Lee
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  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.
  Journal of Biological Chemistry 09/2011; 286(48):41776-85. · 4.77 Impact Factor
• Article: Phosphorylation of a PDZ domain extension modulates binding affinity and interdomain interactions in the PSD-95 MAGUK

  Jun Zhang, Chad M. Petit, David S. King, Andrew L. Lee
  [show abstract] [hide abstract]
  ABSTRACT: Postsynaptic density-95 (PSD-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 (MAGUK) family of proteins, which are defined by the PDZ-SH3-GK domain sequence. We employ 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 reduces ligand binding affinity allosterically and weakens the interaction of PDZ3 with SH3, even though these domains are separated by a ~25-residue linker. Additional phosphorylation at two linker sites further disrupts the interaction, implicating α3 and the linker in tuning interdomain communication. These experiments reveal a novel mode of regulation by detachable PDZ elements and offer a first glimpse at the dynamic interaction of PDZ and SH3-GK domains in MAGUKs.
  Journal of Biological Chemistry 09/2011; · 4.77 Impact Factor