title: Lysine-rich histone (H1) is a lysyl substrate of tissue transglutaminase: possible involvement of transglutaminase in the formation of nuclear aggregates in (CAG)(n)/Q(n) expansion diseases.
abstract: 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.
authors: Department of Biochemistry, Weill Medical College of Cornell University, New York, NY, USA. acooper@burke.org
authors: A J
authors: AJ
authors: Cooper
authors: J
authors: J
authors: Wang
authors: R
authors: R
authors: Pasternack
authors: H L
authors: HL
authors: Fuchsbauer
authors: R K
authors: RK
authors: Sheu
authors: J P
authors: JP
authors: Blass
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002364:Caseins / Q000737:chemistry; D002417:Cattle; D022003:Cell Nucleus Structures / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D005453:Fluorescence; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000737:chemistry; D006168:Guinea Pigs; D006657:Histones / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D006816:Huntington Disease / Q000209:etiology / Q000378:metabolism; D008239:Lysine / Q000737:chemistry / Q000378:metabolism; D046911:Macromolecular Substances; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D013306:Streptomycetaceae / Q000201:enzymology; D011503:Transglutaminases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D019680:Trinucleotide Repeat Expansion; D001615:beta-Endorphin / Q000378:metabolism
chemical_list: D002364:Caseins; D006657:Histones; D046911:Macromolecular Substances; C002087:N,N-dimethylcasein; D010455:Peptides; C097188:polyglutamine; D001615:beta-Endorphin; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D008239:Lysine; D002118:Calcium