Specific non-enzymatic glycation of the rat histone H1 nucleotide binding site in vitro in the presence of AlF4-. A putative mechanism for impaired chromatin function.

We show here that an aluminium derivative, AlF4-, stimulates glycation of histone H1 selectively in the proximity of its nucleotide-binding site. This adduct formation interferes with nucleoside triphosphate hydrolysis by H1 and with nucleotide modulation of H1 DNA binding. The present mode of aluminium action may in part be responsible for its effects on the chromatin structure and expression of tissue-specific genes, and may constitute a mechanism in the pathogenesis of aluminium-induced encephalopathy and in that of Alzheimer's disease, for example.

Interference of AlF4- with nucleotide and DNA binding of rat histone H1 in vitro. Implications for the pathogenesis of Alzheimer's disease.

We demonstrate here that the H2PO4- analogue AlF4- binds to the nucleotide-binding site of rat liver histone H1 in vitro, and interferes with nucleotide recognition and H1 DNA binding. AlF4- may thus compromise the genetically determined pattern of protein synthesis through binding to H1, the general repressor. The present findings are of interest as a number of studies have implicated aluminium as a factor in the pathogenesis of Alzheimer's disease.

Nucleotide recognition by histone H1 involves specific protein structures.

We have reported previously that histone H1 is capable of binding nucleotides such as ATP, GTP, ADP, and GDP in a specific manner. It is demonstrated here using labeling with the uv-crosslinkable ATP analog 8-azido-[alpha-32P]ATP that this ability is a unique characteristic of H1 among the histone proteins. Phosphate analogs such as AlF-4 efficiently counteract the labeling of H1, while they do not compete for labeling of histones H2A, H2B, H3, and H4. Consistent with the assumption that this labeling is due to specific binding, nucleotides competed for the labeling of H1 in a manner similar to labeling of the catalytic subunit of cAMP-dependent protein kinase, casein kinase-II, and heat shock protein-90, all of which are ATP/GTP-binding proteins. The site of nucleotide interaction was subsequently located in a Gly-rich region of H1 which displays homology with the protein kinases, using either radioactive labeling with nucleotide analogs and endoproteinase Glu-C digestion or synthetic peptides corresponding to the putative binding site. The results imply that specific protein structures are involved in nucleotide binding to H1 and that the ability of H1 to bind nucleotides may provide a mechanism for the regulation of eukaryotic gene expression.