Tissue transglutaminase-catalyzed formation of high-molecular-weight aggregates in vitro is favored with long polyglutamine domains:: A possible mechanism contributing to CAG-triplet diseases
Tissue transglutaminase-catalyzed formation of high-molecular-weight aggregates in vitro is favored with long polyglutamine domains:: A possible mechanism contributing to CAG-triplet diseases
复制标题
DOI：
10.1006/abbi.1998.0592
复制
发表时间：
1998-04-15
影响因子：
3.9
通讯作者：
Peluso, G
中科院分区：
文献类型：
--
作者：
Gentile, V;Sepe, C;Peluso, G
为了研究与聚谷氨酰胺扩增相关的“功能毒性增加”可能的生化机制，研究了豚鼠肝组织转谷氨酰胺酶催化多种多胺与聚谷氨酰胺肽共价附着的能力。在测试的多胺中，精胺是最活跃的底物，其次是亚精胺和腐胺。聚谷氨酰胺肽和多胺之间形成的共价交联产生高m -r聚合体——这一过程更有利于长聚谷氨酰胺。在组织转谷氨酰胺酶存在的情况下，纯化的甘油醛-3-磷酸脱氢酶（一种关键的糖酵解酶，与亨廷顿蛋白和齿atorubral- pallidolysian萎缩蛋白的聚谷氨酰胺结构域紧密结合）在体外共价附着在聚谷氨酰胺肽上，导致高m -r聚集体的形成。此外，过量表达人组织转谷氨酰胺酶的Balb-c 3T3成纤维细胞系的内源性甘油醛-3-磷酸脱氢酶与添加到细胞匀浆中的Q（60）多肽形成交联。可能，聚谷氨酰胺结构域的扩展（迄今已知发生在与至少七种神经退行性疾病相关的基因产物中）导致组织中转谷氨酰胺酶催化的与多胺和易感蛋白（如甘油醛-3-磷酸脱氢酶）的交联反应增加/异常。交联异聚物的形成可能导致高m -r蛋白聚集体的沉积，从而导致细胞死亡。(C) 1998学术出版社。
To investigate possible biochemical mechanisms underlying the "toxic gain of function" associated with polyglutamine expansions, the ability of guinea pig liver tissue transglutaminase to catalyze covalent attachments of various polyamines to polyglutamine peptides was examined. Of the polyamines tested, spermine is the most active substrate, followed by spermidine and putrescine. Formation of covalent cross links between polyglutamine peptides and polyamines yields high-M-r aggregates-a process that is favored with longer polyglutamines. In the presence of tissue transglutaminase, purified glyceraldehyde-3-phosphate dehydrogenase (a key glycolytic enzyme that binds tightly to the polyglutamine domains of both huntingtin and dentatorubral-pallidoluysian atrophy proteins) is covalently attached to polyglutamine peptides in vitro, resulting in the formation of high-M-r aggregates. In addition, endogenous glyceraldehyde-3-phosphate dehydrogenase of a Balb-c 3T3 fibroblast cell line overexpressing human tissue transglutaminase forms cross-links with a Q(60) polypeptide added to the cell homogenate. Possibly, expansion of polyglutamine domains (thus far known to occur in the gene products associated with at least seven neurodegenerative diseases) leads to increased/aberrant tissue transglutaminase-catalyzed cross-linking reactions with both polyamines and susceptible proteins, such as glyceraldehyde-3-phosphate dehydrogenase. Formation of cross-linked heteropolymers may lead to deposition of high-M-r protein aggregates, thereby contributing to cell death. (C) 1998 Academic Press.