Collagen processing and molecular chaperones : molecular anatomy based on the domain structures

胶原蛋白加工和分子伴侣：基于域结构的分子解剖学

基本信息

批准号：
13671943
负责人：
NEMOTO Takayuki
金额：
$ 1.98万
依托单位：
Nagasaki University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671943/
关键词：
HSP47 Hsp9Q collagen molecular chaperone domain structure scar 分子シャロペンペプチド結合

项目摘要

Post-translational processing of collagen molecules has been investigated in relation to the function of molecular chaperones. We first investigated the role of Hsp47, a collagen specific molecular chaperone, in scar formation, i.e. excessive and aberrant collagen synthesis triggered by the wounding. We found that Hsp47 as well as type I collagen was not induced in fetal rat wound, in contrast to their enhancement in neonatal rat wound. Hence, we tried to suppress collagen deposition by anti-therapeutic treatment. As a result, scar formation after wounding of neonatal rats was efficiently prevented by an anti-sense oligonucleotide against Hsp47 in vitro (primary-cultured fibroblasts) and in vivo (back wound). These findings strongly suggested that Hsp47 could be a potential target for prevention of scar formation on surgical operations, such as cleft palate.We also investigated the functional mechanism of Hsp90. E. coli HtpG, a bacterial homologue of mammalian Hsp90, was composed of th … More ree domains at the primary structure level as those of human Hsp90. The N-terminal, middle and C-terminal domains were referred to N, M and C domains, respectively. The client-binding activity of Hsp90 was primarily localized in N domain. There were two interactions between the domains : an intramolecular interaction between N and M domains ; and an intermolecular interaction between M and C domains. The latter interaction mediated dimer formation of HSP90. Liberation of the former interaction accompanied the high temperature-induced activation of the client-binding activity of Hsp90 molecular chaperone. That is, the client-binding site located in N domain was concealed by M domain, but heat shock disrupted the interaction. Importance of the interaction between N and M domains was confirmed by expression of aberrant yeast HSP90 (Hsc82), of which M domain could not interact with N domain. We therefore propose the liberation of the intra-molecular interaction as the mechanism of heat-induced activation of Hsp90 molecular chaperone. Less

已经研究了胶原分子的翻译后加工与分子伴侣的功能有关。我们首先研究了HSP47（胶原蛋白特异性分子伴侣）在疤痕形成中的作用，即由获胜而触发的过度和异常胶原蛋白合成。我们发现HSP47和I型胶原蛋白并未在胎儿伤口中诱导，与新生大鼠伤口的增强相比。因此，我们试图通过抗治疗治疗抑制胶原蛋白沉积。结果，新生大鼠缠绕后的疤痕形成是通过对HSP47的体外（原始培养成纤维细胞）和体内（后赢得）有效预防的。这些发现强烈表明，HSP47可能是预防手术手术中疤痕形成的潜在目标，例如cleft裂。我们还研究了HSP90的功能机制。大肠杆菌HTPG是哺乳动物HSP90的细菌同源物，由人类HSP90的主要结构水平上的更多REE域组成。 N末端，中间和C末端结构域分别称为N，M和C结构域。 HSP90的客户结合活动主要定位在N域中。域之间有两种相互作用：N和M域之间的分子内相互作用；以及M和C域之间的分子间相互作用。后来的相互作用介导的HSP90二聚体形成。前相互作用的解放发生在HSP90分子链酮的客户结合活性的高温引起的激活。也就是说，位于N域中的客户结合位点被M域隐藏，但是热冲击破坏了相互作用。 N和M域之间相互作用的重要性通过异常酵母HSP90（HSC82）的表达证实，其中M域无法与N域相互作用。因此，我们提出将分子内相互作用解放为热诱导的Hsp90分子伴侣激活的机制。较少的