Histone H1, which contains about 27%
lysine, is an excellent lysyl donor substrate of Ca(2+)-activated guinea pig liver
tissue transglutaminase as judged by rapid fluorescence enhancement in the presence of the glutaminyl-donor substrate 1-N-(carbobenzoxy-L-glutaminylglycyl)-5-N-(5'N'N'-dimethylamino naphth alenesulfonyl) diamidopentane.
Sodium dodecyl sulfate gel electrophoresis of a 30-min reaction mixture revealed the presence of fluorescent high-M(r) aggregates, which are also formed when
histone H1 is incubated solely with activated
tissue transglutaminase. Aggregate formation is even more pronounced when
histone H1 is incubated with activated
tissue transglutaminase and
dimethylcasein (glutaminyl donor only). The findings suggest not only that
histone H1 is an especially good lysyl substrate of
tissue transglutaminase, but that it is also a glutaminyl substrate.
Histone H1 is a good lysyl substrate of
transglutaminase purified from Streptoverticillium mobaraense, suggesting that the ability of
histone H1 to act as a
transglutaminase lysyl substrate is widespread. In agreement with previous studies, it was found that human
beta-endorphin is a moderately good substrate of
tissue transglutaminase. At least 8
neurodegenerative diseases, including
Huntington's disease, are caused by (CAG)(n) expansions in the genome and by an expansion of the corresponding
polyglutamine domain within the expressed, mutated
protein.
Polyglutamine domains are excellent substrates of liver and brain
transglutaminases. A hallmark of many of the (CAG)(n)/
polyglutamine expansion diseases is the presence of
polyglutamine-containing aggregates within the cytosol and nuclei of affected neurons.
Transglutaminase activity occurs in both of these compartments in human brain. In future studies, it will be important to determine whether
transglutaminases play a role in (1) cross-linking of
histone H1 to glutaminyl donors (including
polyglutamine domains) in nuclear
chromatin, (2) the formation of nuclear aggregates in (CAG)(n)/
polyglutamine expansion diseases, (3)
DNA laddering and cell death in
neurodegenerative diseases and (4) depletion of
neuropeptides in vulnerable regions of
Huntington's disease brain.