HSP90 AND THE ENDOTHELIAL NITRIC OXIDE SYNTHASE

HSP90 和内皮一氧化氮合酶

• 批准号: 6627505
• 负责人: MICHAEL B HARRIS
• 金额: $ 4.64万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-12-31 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6627505
• 关键词: enzyme activity; heat shock proteins; nitric oxide synthase; protein protein interaction; protein structure function; vascular endothelium

eNOS, as a synthesizer of nitric oxide (NO), plays an important role in the regulation of vascular tone, platelet and leukocyte adhesion to the endothelium, endothelin-1 generation, vascular smooth muscle proliferation, and vascular lesion formation. Recently, it has been demonstrated that eNOS directly binds to the 90 kDa heat shock proteins, Hsp90, however, the interacting domains in the two proteins have not been identified. Increased interaction of Hsp90 with eNOS has been demonstrated with a variety of treatments and is associated with increased eNOS activity, which can be blocked by the specific inhibitor of Hsp90, geldanamycin. The mechanism for Hsp90 activation of eNOS is unknown. Due to its role as a molecular chaperone, Hsp90 may stabilize and prevent the aggregation of partially folded or dimeric forms of eNOS, thereby increasing the overall activity. In addition, Hsp90 may alter the three dimensional structure of eNOS and affect binding of important co-factors such as calmodulin (CaM). Therefore, the goals of this project are two-fold, to map the interacting domains between Hsp90 and eNOS and to examine potential mechanisms by which Hsp90 upregulates eNOS activity.

eNOS作为一氧化氮（NO）的合成者，在调节血管张力、血小板和白细胞粘附内皮、内皮素-1生成、血管平滑肌增殖和血管病变形成等方面发挥重要作用。最近有研究表明，eNOS可直接与90 kDa热休克蛋白Hsp90结合，但这两种蛋白的相互作用结构域尚未确定。Hsp90与eNOS的相互作用增加已经在多种治疗中得到证实，并与eNOS活性增加相关，而eNOS活性可以被Hsp90的特异性抑制剂格尔达霉素阻断。Hsp90激活eNOS的机制尚不清楚。由于其作为分子伴侣的作用，Hsp90可以稳定和阻止部分折叠或二聚体形式的eNOS聚集，从而提高整体活性。此外，Hsp90可能改变eNOS的三维结构，影响钙调素（CaM）等重要辅因子的结合。因此，本项目的目标是双重的，绘制Hsp90和eNOS之间的相互作用域，并研究Hsp90上调eNOS活性的潜在机制。