Structural Basis for Asymmetric Association of the βPIX Coiled Coil and Shank PDZ |
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Authors: | Young Jun Im Gil Bu Kang Jun Hyuck Lee Hye Eun Song Woo Keun Song Soo Hyun Eom |
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Affiliation: | 1 College of Pharmacy, Chonnam National University, Gwangju 500-757, South Korea 2 Department of Life Science, Cell Dynamics Research Center, Gwangju Institute of Science and Technology, Gwangju 500-712, South Korea 3 Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Guseong-dong, Daejeon 305-701, South Korea 4 School of Biological Sciences, Seoul National University, Seoul 151-742, South Korea |
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Abstract: | βPIX (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 βPIX and the Shank PDZ domain. The coiled-coil (CC) domain upstream of the PDZ binding motif allows multimerization of βPIX, which is important for its physiological functions. We have solved the crystal structure of the βPIX CC-Shank PDZ complex and determined the stoichiometry of complex formation. The βPIX CC forms a 76-Å-long parallel CC trimer. Despite the fact that the βPIX CC exposes three PDZ binding motifs in the C-termini, the βPIX trimer associates with a single Shank PDZ. One of the C-terminal ends of the CC forms an extensive β-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 βPIX 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 βPIX trimer. The structure shows canonical class I PDZ binding with a β-sheet interaction extending to position − 6 of βPIX. The βB-βC loop of Shank PDZ undergoes a conformational change upon ligand binding to form the β-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 βPIX CC and Shank PDZ. |
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Keywords: | PIX p21-activated kinase interacting exchange factor CC coiled coil SH3 Src homology 3 GIT G-protein-coupled receptor kinase interacting protein PAK p21-activated kinase GKAP guanylate-kinase-associated protein MAD multiple anomalous dispersion NTA nitrilotriacetic acid LI loop insertion |
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