title: Structural basis for asymmetric association of the betaPIX coiled coil and shank PDZ.
abstract: betaPIX (p21-activated kinase interacting exchange factor) and Shank/ProSAP protein form a complex acting as a protein scaffold that integrates signaling pathways and regulates postsynaptic structure. Complex formation is mediated by the C-terminal PDZ binding motif of betaPIX and the Shank PDZ domain. The coiled-coil (CC) domain upstream of the PDZ binding motif allows multimerization of betaPIX, which is important for its physiological functions. We have solved the crystal structure of the betaPIX CC-Shank PDZ complex and determined the stoichiometry of complex formation. The betaPIX CC forms a 76-A-long parallel CC trimer. Despite the fact that the betaPIX CC exposes three PDZ binding motifs in the C-termini, the betaPIX trimer associates with a single Shank PDZ. One of the C-terminal ends of the CC forms an extensive beta-sheet interaction with the Shank PDZ, while the other two ends are not involved in ligand binding and form random coils. The two C-terminal ends of betaPIX have significantly lower affinity than the first PDZ binding motif due to the steric hindrance in the C-terminal tails, which results in binding of a single PDZ domain to the betaPIX trimer. The structure shows canonical class I PDZ binding with a beta-sheet interaction extending to position -6 of betaPIX. The betaB-betaC loop of Shank PDZ undergoes a conformational change upon ligand binding to form the beta-sheet interaction and to accommodate the bulky side chain of Trp -5. This structural study provides a clear picture of the molecular recognition of the PDZ ligand and the asymmetric association of betaPIX CC and Shank PDZ.
authors.affiliation: College of Pharmacy, Chonnam National University, Gwangju 500-757, South Korea. youngjun.im@gmail.com <youngjun.im@gmail.com>
authors.forename: Young Jun
authors.initials: YJ
authors.lastname: Im
authors.forename: Gil Bu
authors.initials: GB
authors.lastname: Kang
authors.forename: Jun Hyuck
authors.initials: JH
authors.lastname: Lee
authors.forename: Kyoung Ryoung
authors.initials: KR
authors.lastname: Park
authors.forename: Hye Eun
authors.initials: HE
authors.lastname: Song
authors.forename: Eunjoon
authors.initials: E
authors.lastname: Kim
authors.forename: Woo Keun
authors.initials: WK
authors.lastname: Song
authors.forename: Dongeun
authors.initials: D
authors.lastname: Park
authors.forename: Soo Hyun
authors.initials: SH
authors.lastname: Eom
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry* / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D051381:Rats; D064067:Rho Guanine Nucleotide Exchange Factors
chemical_list: D002352:Carrier Proteins; D020662:Guanine Nucleotide Exchange Factors; C523118:Lzts3 protein, rat; D008565:Membrane Proteins; D064067:Rho Guanine Nucleotide Exchange Factors