Interaction/Oligomerization of Nucleoside Diphosphate Kinase Isoforms in Pathological Processes

病理过程中核苷二磷酸激酶亚型的相互作用/寡聚化

• 批准号: 512541541
• 负责人: Professor Dr. Thomas Wieland, Ph.D.
• 金额: --
• 依托单位: Abteilung Experimentelle Pharmakologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/512541541?language=en
• 关键词: Interaction; Oligomerization; Nucleoside; Diphosphate; Kinase

Nucleoside diphosphate kinases (NDPK) are enzymes that catalyze the transfer of terminal phosphate groups, mainly from adenosine triphosphate (ATP), to nucleoside diphosphates (NDP) and thus replenish nucleoside triphosphate (NTP) pools required for a wide variety of cellular processes. The class I subfamily, consisting of the isoforms NDPK A, B, C, and D, possess enzymatic activity and are known to form homo-and hetero-hexamers. Whereas NDPK D has a specific role in the mitochondrial inner membrane, the role of the other three isoforms, of which NDPK C is less abundantly expressed than NDPK A and NDPK B, is less well defined. In addition to its role in contributing to the upkeep of the cellular NTP pool, NDPK B has specific cellular functions in cell growth, differentiation, and signaling. We have previously established the essential role of NDPK B in cellular glucose metabolism, especially in the hexosamine biosynthesis pathway and protein O-GlcNAcylation. Additionally we reported that the formation of an NDPK B and NDPK C complex governs its translocation to the plasma membrane and its interaction with heterotrimeric G proteins, which contributes to the dysregulation of cardiomyocyte cAMP formation in human heart failure. As our preliminary data point to a role of NDPK B in cardiomyopathy by regulating cardiac protein O-GlcNAcylation, we hypothesize that a cooperation or interaction of NDPK B and NDPK C might be important in the development of diabetic cardiomyopathy. This proposal therefore aims (1) to elucidate the role and interaction of NDPK B and NDPK C in metabolic cardiomyopathy by using the streptozotocin-induced diabetes model in wild type and NDPK B deficient mice, (2) to investigate the interaction/oligomerization of NDPK B and NDPK C in cellular glucose metabolisms in different cardiac cell types in vitro.

核苷二磷酸酶(NDPK)是催化末端磷酸基团(主要是从三磷酸腺苷(ATP)转移到核苷二磷酸(NDP)，从而补充广泛的细胞过程所需的核苷三磷酸(NTP)池的酶。I类亚家族由NDPK A、B、C和D四种异构体组成，具有酶活性，可形成同源和异源六聚体。虽然NDPK D在线粒体内膜上有特定的作用，但其他三种异构体的作用还不是很清楚，其中NDPK C的表达低于NDPK A和NDPK B。NDPK B除了在维持细胞NTP池方面发挥作用外，还在细胞生长、分化和信号转导方面具有特定的细胞功能。我们已经确定了NDPK B在细胞葡萄糖代谢中的重要作用，特别是在氨基己糖的生物合成途径和蛋白质O-GlcN酰化过程中。此外，我们还报道了NDPK B和NDPK C复合体的形成调节了它向质膜的移位以及它与异源三聚体G蛋白的相互作用，这导致了心力衰竭时心肌细胞cAMP形成的失调。由于我们的初步数据表明NDPK B通过调节心肌蛋白O-GlcN酰化在心肌病中发挥作用，我们推测NDPK B和NDPK C的协同或相互作用在糖尿病心肌病的发生发展中可能是重要的。因此，本研究的目的是：(1)利用链脲佐菌素诱导的小鼠糖尿病模型，探讨NDPK B和NDPK C在代谢性心肌病中的作用和相互作用；(2)研究NDPK B和NDPK C在体外不同类型心肌细胞葡萄糖代谢中的相互作用和相互作用。