title: Crystal structure of the Shank PDZ-ligand complex reveals a class I PDZ interaction and a novel PDZ-PDZ dimerization.
abstract: 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-A 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 beta B/beta C loop and N-terminal beta A strands, suggesting a novel model of PDZ-PDZ homodimerization. This implies that antiparallel dimerization through the N-terminal beta A 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.
authors.affiliation: Department of Life Science, Kwangju Institute of Science and Technology, Gwangju 500-712, South Korea.
authors.forename: Young Jun
authors.initials: YJ
authors.lastname: Im
authors.forename: Jun Hyuck
authors.initials: JH
authors.lastname: Lee
authors.forename: Seong Ho
authors.initials: SH
authors.lastname: Park
authors.forename: Soo Jeong
authors.initials: SJ
authors.lastname: Park
authors.forename: Seong-Hwan
authors.initials: SH
authors.lastname: Rho
authors.forename: Gil Bu
authors.initials: GB
authors.lastname: Kang
authors.forename: Eunjoon
authors.initials: E
authors.lastname: Kim
authors.forename: Soo Hyun
authors.initials: SH
authors.lastname: Eom
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001224:Aspartic Acid / Q000737:chemistry; D002352:Carrier Proteins / Q000737:chemistry*; D018360:Crystallography, X-Ray; D019281:Dimerization; D004926:Escherichia coli / Q000378:metabolism; D006860:Hydrogen Bonding; D007930:Leucine / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D017386:Sequence Homology, Amino Acid
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D008024:Ligands; D009419:Nerve Tissue Proteins; D010455:Peptides; C120531:Shank1 protein, rat; C033652:postsynaptic density proteins; D001224:Aspartic Acid; D007930:Leucine