Transglutaminase-catalyzed inactivation of glyceraldehyde 3-phosphate dehydrogenase and alpha-ketoglutarate dehydrogenase complex by polyglutamine domains of pathological length
Transglutaminase-catalyzed inactivation of glyceraldehyde 3-phosphate dehydrogenase and alpha-ketoglutarate dehydrogenase complex by polyglutamine domains of pathological length
复制标题
DOI：
10.1073/pnas.94.23.12604
复制
发表时间：
1997-11-11
影响因子：
11.1
通讯作者：
Blass, JP
中科院分区：
文献类型：
--
作者：
Cooper, AJL;Sheu, KFR;Blass, JP
一些成人起病的神经退行性疾病是由编码区扩大的CAG三联体重复序列和表达蛋白中扩大的多谷氨酰胺(A)结构域基因引起的。通常，在临床患者中，n大于或等于40。甘油醛3-磷酸脱氢酶与四种Q(N)病蛋白紧密结合，但这种相互作用的意义尚不清楚。我们现在报道，纯化的甘油醛3-磷酸脱氢酶在含有病理长度的a结构域的谷胱甘肽S转移酶的存在下被组织转谷氨酰胺酶灭活(n=62或81)。当含有较短的Q(N)结构域(n=0或10)时，组织转谷氨酰胺酶对脱氢酶的抑制作用较小。纯化的cr-酮戊二酸脱氢酶复合体也可被含有病理长度a结构域的组织转谷氨酰胺酶和谷胱甘肽S转移酶所灭活(n=62或81)。结果提示，在CAG/Q(N)扩张性疾病中，组织转谷氨酰胺酶催化的共价连接涉及更大的多Q结构域，可能会扰乱大脑的能量代谢。
Several adult-onset neurodegenerative diseases are caused by genes with expanded CAG triplet repeats within their coding regions and extended polyglutamine (a) domains within the expressed proteins. Generally, in clinically affected individuals n greater than or equal to 40. Glyceraldehyde 3-phosphate dehydrogenase binds tightly to four Q(n) 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 a domain of pathological length (n = 62 or 81). The dehydrogenase is less strongly inhibited by tissue transglutaminase in the presence of constructs containing shorter Q(n) domains (n = 0 or 10). Purified cr-ketoglutarate dehydrogenase complex also is inactivated by tissue transglutaminase plus glutathione S-transferase constructs containing pathological-length a 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/Q(n) expansion diseases.