Crystal structure of the Shank PDZ-ligand complex reveals a class IPDZ interaction and a novel PDZ-PDZ dimerization

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The Shank/proline-rich synapse-associated protein family of multidomain proteins is known to play an important role in the organization of synaptic multiprotein complexes. For instance, the Shank PDZ domain binds to the C termini of guanylate kinase-associated proteins, which in turn interact with the guanylate kinase domain of postsynaptic density-95 scaffolding proteins. Here we describe the crystal structures of Shank1 PDZ in its peptide free form and in complex with the C-terminal hexapeptide (EAQTRL) of guanylate kinase-associated protein (GKAP1a) determined at 1.8- and 2.25-Angstrom resolutions, respectively. The structure shows the typical class I PDZ interaction of PDZ-peptide complex with the consensus sequence -X-(Thr/Ser)-X-Leu. In addition, Asp-634 within the Shank1 PDZ domain recognizes the positively charged Arg at - 1 position and hydrogen bonds, and salt bridges between Arg-607 and the side chains of the ligand at - 3 and - 5 positions contribute further to the recognition of the peptide ligand. Remarkably, whether free or complexed, Shank1 PDZ domains form dimers with a conserved betaB/betaC loop and N-terminal betaA strands, suggesting a novel model of PDZ-PDZ homodimerization. This implies that antiparallel dimerization through the N-terminal betaA strands could be a common configuration among PDZ dimers. Within the dimeric structure, the two-peptide binding sites are arranged so that the N termini of the bound peptide ligands are in close proximity and oriented toward the 2-fold axis of the dimer. This configuration may provide a means of facilitating dimeric organization of PDZ-target assemblies.
Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Issue Date
2003-11
Language
English
Article Type
Article
Keywords

POSTSYNAPTIC DENSITY PROTEINS; SYNAPTIC PROTEINS; CARBOXYL-TERMINI; BETA-PIX; FAMILY; DOMAIN; RECOGNITION; MULTIMERIZATION; ASSOCIATION; REGULATOR

Citation

JOURNAL OF BIOLOGICAL CHEMISTRY, v.278, no.48, pp.48099 - 48104

ISSN
0021-9258
URI
http://hdl.handle.net/10203/82089
Appears in Collection
BS-Journal Papers(저널논문)
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