Post-translational regulation of BATF.

摘要

BATF is phosphorylated on several residues including serine 43 and threonine 48 within the DNA Binding Domain (DBD) and hinge regions, respectively. To model phosphorylation events within the DBD of BATF, serine 43 and threonine 48 were replaced by aspartate residues. BATF (S43D) retains the ability to dimerize with Jun class proteins and reduce AP-1 transactivation potential, but is completely deficient in DNA binding ability. Thus, it appears that phosphorylation of BATF at serine 43 converts the protein from a DNA-binding to a non-DNA-binding inhibitor of AP-1 activity.{09}Modeling phosphorylation within the hinge region of BATF at position 48 induces strong homodimerization but has no affect on its capacity to heterodimenze with Jun. Interestingly, BATF (T48D) homodimers are unable to bind target DNA elements, whereas BATF (T48D):Jun heterodimers retain this ability. These biochemical properties of BATF (T48D) culminate in a reduced capacity to compete with Fos for Jun binding resulting in an inability to efficiently inhibit AP-1 transactivation. This represents the first example of a phosphorylation event occurring within the bZIP hinge region resulting in stabilization of the homodimer. In studying the mechanism by which modeling phosphorylation at BATF position 48 increases its ability to homodimerize, an investigation of the determinants for dimerization affinity and specificity between bZIP factors was initiated. These determinants have been used to evaluate all other bZIP factors in the human genome as potential dimer partners for BATF. This analysis revealed potential dimer partners from C/EBP, ATF2, and PAR families. Some bZIP proteins predicted to favorably or unfavorably interact with BATF have been validated experimentally. Predicted dimerization analyses were expanded and genome-wide annotation and dimerization evaluation of bZIP factors found in the Arabidopsis thaliana and Giardia lamblia genomes was performed. Using novel methodology to map interactions within the complex dimerization networks of bZIP factors, several observations are made regarding the differences in these networks, between species. Furthermore, comparison of these networks across three eukaryotic kingdoms allows for insight into the origins of bZIP factors.