Intrinsic protein-protein interaction-mediated and chaperonin-assisted sequential assembly of stable bardet-biedl syndrome protein complex, the BBSome.
Intrinsic protein-protein interaction-mediated and chaperonin-assisted sequential assembly of stable bardet-biedl syndrome protein complex, the BBSome.
复制标题
DOI：
10.1074/jbc.m112.341487
复制
发表时间：
2012-06-08
期刊：
影响因子：
--
通讯作者：
Sheffield VC
中科院分区：
文献类型：
--
作者：
Zhang Q;Yu D;Seo S;Stone EM;Sheffield VC
背景：Bardet-Biedl综合征蛋白形成一种称为BBSome的复合物。BBSome组装的细节尚不清楚。结果：BBSome通过内在的蛋白-蛋白相互作用进行组装，其中一些与细胞质伴侣蛋白有关。结论：BBSome的组装是一个受调控的逐步过程。意义：了解BBSome的组装过程可能有助于更好地了解纤毛相关疾病的分子机制。Bardet-Biedl综合征（BBS）中发现的肥胖、视网膜变性、多指畸形、肾脏异常、认知障碍、高血压和糖尿病的多效性特征使该疾病成为识别人类常见疾病分子机制的重要模型疾病。迄今为止，已经报道了16个BBS基因，其中7个（BBS1、2、4、5、7、8和9）编码形成称为BBSome复合物的蛋白质。BBSome的功能涉及睫状膜的生物发生。另外三个BBS基因（BBS6、BBS10和BBS12）与II型伴侣蛋白具有同源性，并与CCT/TRiC蛋白和BBS7相互作用，形成称为BBS-伴侣蛋白复合物的复合物。这个复合体是BBSome组装所必需的。人们对BBSome的形成过程和调控知之甚少。我们利用BBS蛋白的点突变和空等位基因破坏BBSome的组装，导致BBSome组装中间体的积累。通过对BBS7组装中间体的表征，我们发现bb -伴侣蛋白复合物在BBS7的稳定性中起作用。BBS7与BBS2相互作用，成为BBS7-BBS2- bbs9组装中间体的一部分，因为它形成了BBSome的核心，所以被称为BBSome核心复合体。BBS1, BBS5, BBS8，最后BBS4加入BBSome核心，形成完整的BBSome。
Background: Bardet-Biedl syndrome proteins form a complex known as the BBSome. The details of BBSome assembly are unknown. Results: The BBSome is assembled via intrinsic protein-protein interactions, some of which involve cytoplasmic chaperonins. Conclusion: BBSome assembly is a regulated stepwise process. Significance: Understanding the assembly process of the BBSome might help to better understand the molecular mechanisms involved in cilia-related diseases. The pleiotropic features of obesity, retinal degeneration, polydactyly, kidney abnormalities, cognitive impairment, hypertension, and diabetes found in Bardet-Biedl syndrome (BBS) make this disorder an important model disorder for identifying molecular mechanisms involved in common human diseases. To date, 16 BBS genes have been reported, seven of which (BBS1, 2, 4, 5, 7, 8, and 9) code for proteins that form a complex known as the BBSome. The function of the BBSome involves ciliary membrane biogenesis. Three additional BBS genes (BBS6, BBS10, and BBS12) have homology to type II chaperonins and interact with CCT/TRiC proteins and BBS7 to form a complex termed the BBS-chaperonin complex. This complex is required for BBSome assembly. Little is known about the process and the regulation of BBSome formation. We utilized point mutations and null alleles of BBS proteins to disrupt assembly of the BBSome leading to the accumulation of BBSome assembly intermediates. By characterizing BBSome assembly intermediates, we show that the BBS-chaperonin complex plays a role in BBS7 stability. BBS7 interacts with BBS2 and becomes part of a BBS7-BBS2-BBS9 assembly intermediate referred to as the BBSome core complex because it forms the core of the BBSome. BBS1, BBS5, BBS8, and finally BBS4 are added to the BBSome core to form the complete BBSome.