Reduction/oxidation-phosphorylation control of DNA binding in the bZIP dimerization network

Abstract

Background: bZIPs are transcription factors that are found throughout the eukarya from fungi to flowering plants and mammals. They contain highly conserved basic region (BR) and leucine zipper (LZ) domains and often function as environmental sensors. Specifically, bZIPs frequently have a role in mediating the response to oxidative stress, a crucial environmental signal that needs to be transduced to the gene regulatory network.

Results: Based on sequence comparisons and experimental data on a number of important bZIP transcription factors, we predict which bZIPs are under redox control and which are regulated via protein phosphorylation. By integrating genomic, phylogenetic and functional data from the literature, we then propose a link between oxidative stress and the choice of interaction partners for the bZIP proteins.

Conclusion: This integration permits the bZIP dimerization network to be interpreted in functional terms, especially in the context of the role of bZIP proteins in the response to environmental stress. This analysis demonstrates the importance of abiotic factors in shaping regulatory networks.

Figure 1

Multiple alignment of the DNA-binding BR of human bZIPs. Each protein sequence is a representative of a bZIP family. The first part of the protein name designates the family, while the second part designates the specific protein. The sequences are coloured by residue, using the default colouring scheme of ClustalX.

Figure 2

Representation of the phosphorylation and redox control of DNA binding in bZIP dimers. Red-dotted monomers contain C19, whereas blue-dotted monomers contain either S19 or Y19. C-C type dimers are very sensitive to oxidative stress and cannot bind to DNA under these conditions. C-S and C-Y dimers are moderately sensitive to oxidative stress. Furthermore, C-S and C-Y dimers can be phosphorylated at S19 or Y19 to totally abolish DNA binding. S-S and S-Y dimers also totally abolish DNA binding when phosphorylated at any of the S19 or Y19 residues. Phosphorylation behaves dominantly. To simplify the graph, we excluded A19 monomers and dimers. A-A type dimers are neither controlled by redox nor by phosphorylation. S-A type dimers are controlled by phosphorylation. No C-A or Y-A type dimers have been observed, see [19].

Figure 3

Neighbour joining tree of the Basic region of human, fly, cnidarian and fungal bZIPs. The colouring of the clades is based on the amino acid at position 19 (green – tyrosine; red – cysteine; blue – serine; yellow – phenylalanine).

Figure 4

Proportional tree of the human and fruit fly bZIP basic regions. Additional information is added for the five amino acids in the BR that make contact with DNA [5], the presence of a phosphorylation or redox mechanism (depending on the amino acid at position 19) and the dimerizing partners of each protein. Blue circles and diamonds represent human bZIPs, and red circles and diamonds represent Drosophila bZIPs for which interaction data are available. Circles represent proteins that can homodimerize, while diamonds represent proteins that cannot homodimerize. The arcs to the right that connect them represent heterodimerization. The colours of the arcs represent the type of heterodimer formed (red, C-C; green, C-X; blue, S-S and S-Y).

Figure 5

The bZIP dimerization network, integrating phosphorylation and redox information. Circles, diamonds and rectangles represent proteins that can homodimerize, cannot homodimerize, or for which no interaction data are available respectively. Proteins that contain C19 are coloured red, proteins that contain S19 or Y19 are coloured blue and proteins that contain A19 are coloured black. Interactions (vertices) that form C-C type dimers are coloured red, interactions that form C-X type dimers are coloured green, interactions that form S-S, S-Y or S-A type dimers are coloured blue. The bottom left diagram depicts the distribution of connectivity for the bZIP network, which does not appear to decay in a power-law.