title: Transglutaminase-catalyzed inactivation of glyceraldehyde 3-phosphate dehydrogenase and alpha-ketoglutarate dehydrogenase complex by polyglutamine domains of pathological length.
abstract: Several adult-onset neurodegenerative diseases are caused by genes with expanded CAG triplet repeats within their coding regions and extended polyglutamine (Qn) domains within the expressed proteins. Generally, in clinically affected individuals n >/= 40. Glyceraldehyde 3-phosphate dehydrogenase binds tightly to four Qn disease proteins, but the significance of this interaction is unknown. We now report that purified glyceraldehyde 3-phosphate dehydrogenase is inactivated by tissue transglutaminase in the presence of glutathione S-transferase constructs containing a Qn domain of pathological length (n = 62 or 81). The dehydrogenase is less strongly inhibited by tissue transglutaminase in the presence of constructs containing shorter Qn domains (n = 0 or 10). Purified alpha-ketoglutarate dehydrogenase complex also is inactivated by tissue transglutaminase plus glutathione S-transferase constructs containing pathological-length Qn domains (n = 62 or 81). The results suggest that tissue transglutaminase-catalyzed covalent linkages involving the larger poly-Q domains may disrupt cerebral energy metabolism in CAG/Qn expansion diseases.
authors.affiliation: Department of Biochemistry, Cornell University Medical College, New York, NY 10021, USA. ajlc@mail.med.cornell.edu
authors.forename: A J
authors.initials: AJ
authors.lastname: Cooper
authors.forename: K R
authors.initials: KR
authors.lastname: Sheu
authors.forename: J R
authors.initials: JR
authors.lastname: Burke
authors.forename: O
authors.initials: O
authors.lastname: Onodera
authors.forename: W J
authors.initials: WJ
authors.lastname: Strittmatter
authors.forename: A D
authors.initials: AD
authors.lastname: Roses
authors.forename: J P
authors.initials: JP
authors.lastname: Blass
mesh_terms: D000818:Animals; D001665:Binding Sites; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006168:Guinea Pigs; D007655:Ketoglutarate Dehydrogenase Complex / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000201:enzymology / Q000235:genetics; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011817:Rabbits; D013379:Substrate Specificity; D011503:Transglutaminases / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D010446:Peptide Fragments; C068142:glyceraldehyde 3-phosphate dehydrogenase (304-313); D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D007655:Ketoglutarate Dehydrogenase Complex; D011503:Transglutaminases