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1 Natural Products and Cancer Biology Program, Cancer Research Center of Hawaii, University of Hawaii at Manoa, Honolulu, Hawaii 96813, USA
2 Department of Microbiology, University of Hawaii at Manoa, Honolulu, Hawaii 96822, USA
3 Maui High Performance Computing Center, Kihei, Maui, Hawaii 96753, USA
4 Center for Genomics, Proteomics, and Bioinformatics Research Initiative, University of Hawaii at Manoa, Honolulu, Hawaii 96822, USA
(RECEIVED February 16, 2006; FINAL REVISION June 18, 2006; ACCEPTED July 24, 2006)
The interaction of cellular proteins with the gap junction protein Connexin43 (Cx43) is thought to form a dynamic scaffolding complex that functions as a platform for the assembly of signaling, structural, and cytoskeletal proteins. A high stringency Scansite search of rat Cx43 identified the motif containing Ser373 (S373) as a 14-3-3 binding site. The S373 motif and the second best mode-1 motif, containing Ser244 (S244), are conserved in rat, mouse, human, chicken, and bovine, but not in Xenopus or zebrafish Cx43. Docking studies of a mouse/rat 14-3-3
homology model with the modeled phosphorylated S373 or S244 peptide ligands or their serine-to-alanine mutants, S373A or S244A, revealed that the pS373 motif facilitated a greater number of intermolecular contacts than the pS244 motif, thus supporting a stronger 14-3-3 binding interaction with the pS373 motif. The alanine substitution also reduced more than half the number of intermolecular contacts between 14-3-3 and the S373 motif, emphasizing the phosphorylation dependence of this interaction. Furthermore, the ability of the wild-type or the S244A GST-Cx43 C-terminal fusion protein, but not the S373A fusion protein, to interact with either 14-3-3 or 14-3-3
in GST pull-down experiments clearly demonstrated that the S373 motif mediates the direct interaction between Cx43 and 14-3-3 proteins. Blocking growth factor–induced Akt activation and presumably any Akt-mediated phosphorylation of the S373 motif in ROSE 199 cells did not prevent the down-regulation of Cx43-mediated cell–cell communication, suggesting that an Akt-mediated interaction with 14-3-3 was not involved in the disruption of Cx43 function.
Keywords: Connexin43; 14-3-3; protein–protein interactions; homology modeling; phosphorylation; mode-1 binding motif
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