Phosphorylation of HMG‐I by Protein Kinase C Attenuates Its Binding Affinity to the Promoter Regions of Protein Kinase C γ and Neurogranin/RC3 Genes

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Abstract
A 20‐kDa DNA‐binding protein that binds the AT‐rich sequences within the promoters of the brain‐specific protein kinase C (PKC) γ and neurogranin/RC3 genes has been characterized as chromosomal nonhistone high‐mobility‐group protein (HMG)‐I. This protein is a substrate of PKC α, β, γ, and δ but is poorly phosphorylated by PKC ε and ζ. Two major (Ser44 and Ser64) and four minor phosphorylation sites have been identified. The extents of phosphorylation of Ser44 and Ser64 were 1:1, whereas those of the four minor sites all together were 100‐fold reduction in binding affinity. The two cdc2 kinase phosphorylation sites of HMG‐I are adjacent to the N terminus of two of the three predicted DNA‐binding domains. In comparison, one of the major PKC phosphorylation sites, Ser64, is adjacent to the C terminus of the second DNA‐binding domain, whereas Ser44 is located within the spanning region between the first and second DNA‐binding domains. The current results suggest that phosphorylation of the mammalian HMG‐I by PKC alone or in combination with cdc2 kinase provides an effective mechanism for the regulation of HMG‐I function.