BiP clustering facilitates protein folding in the endoplasmic reticulum.
BiP clustering facilitates protein folding in the endoplasmic reticulum.
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DOI：
10.1371/journal.pcbi.1003675
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发表时间：
2014-07
影响因子：
4.3
通讯作者：
Petzold L
中科院分区：
文献类型：
--
作者：
Griesemer M;Young C;Robinson AS;Petzold L
伴侣BiP参与内质网（ER）内的几个调节过程：易位，蛋白质折叠和ER相关降解。为了促进蛋白质折叠，已经提出了一种称为熵拉的合作机制，以证明多个BiP分子如何与新生和未折叠蛋白质结合的分子水平的理解。最近，实验证据表明，在S的核和外周ER的BiP的空间异质性。酿酒酵母（通常称为“簇”）。在这里，我们开发了一个模型来评估占多个BiP分子结合肽的潜在优势，同时提出BiP的空间异质性可能会增强蛋白质的折叠和成熟。模拟场景以测量将多个伴侣分子结合到肽的有效性。使用两个指标：折叠效率和伴侣蛋白的成本，我们确定，单结合位点模型实现了更高的效率比模型的特点是多个结合位点，在缺乏协同性。然而，由于熵拉动，多个分子伴侣协同作用以促进折叠蛋白质的再溶解和最终产量。由于协同性，多结合位点模型使用较少的BiP分子，并保持了较高的折叠效率比单结合位点模型。这些insilico调查显示，集群的BiP分子结合到未折叠的蛋白质，可以提高折叠效率，通过合作行动，通过熵拉。蛋白质的错误折叠对阿尔茨海默氏症、帕金森氏症、癌症和糖尿病等疾病具有重要意义。一旦错误折叠，蛋白质倾向于结合成对细胞构成毒性威胁的聚集体。分子伴侣是通过毒性寡聚体的解离和适当的（再）折叠将细胞从这些失调蛋白的积累中拯救出来的蛋白质。内质网（ER）是一种细胞器，在早期分泌途径中充当蛋白质转运、折叠和成熟的伴侣活动的舞台。我们已经开发了一个计算模型来研究潜在的机制，使多个ER驻留分子协同工作，有效地折叠肽和运输新生蛋白质穿过ER膜。虽然以前的模型集中在分子伴侣与肽的相互作用，我们已经探讨了分子伴侣分子之间的协同作用，以协助蛋白质的折叠和成熟的影响。我们发现分子伴侣的合作导致了更高的产量折叠分子相比，当分子伴侣结合肽在1∶1的化学计量。我们的结论是，分子伴侣的聚集或多重结合可能有助于蛋白质在体内的折叠。
The chaperone BiP participates in several regulatory processes within the endoplasmic reticulum (ER): translocation, protein folding, and ER-associated degradation. To facilitate protein folding, a cooperative mechanism known as entropic pulling has been proposed to demonstrate the molecular-level understanding of how multiple BiP molecules bind to nascent and unfolded proteins. Recently, experimental evidence revealed the spatial heterogeneity of BiP within the nuclear and peripheral ER of S. cerevisiae (commonly referred to as ‘clusters’). Here, we developed a model to evaluate the potential advantages of accounting for multiple BiP molecules binding to peptides, while proposing that BiP's spatial heterogeneity may enhance protein folding and maturation. Scenarios were simulated to gauge the effectiveness of binding multiple chaperone molecules to peptides. Using two metrics: folding efficiency and chaperone cost, we determined that the single binding site model achieves a higher efficiency than models characterized by multiple binding sites, in the absence of cooperativity. Due to entropic pulling, however, multiple chaperones perform in concert to facilitate the resolubilization and ultimate yield of folded proteins. As a result of cooperativity, multiple binding site models used fewer BiP molecules and maintained a higher folding efficiency than the single binding site model. These insilico investigations reveal that clusters of BiP molecules bound to unfolded proteins may enhance folding efficiency through cooperative action via entropic pulling. The misfolding of proteins carries important implications for diseases such as Alzheimer's, Parkinson's, cancer, and diabetes. Once misfolded, proteins tend to associate into aggregates that pose a toxic threat to the cell. Chaperones are proteins that rescue the cell from an accumulation of these maladjusted proteins through dissociation of toxic oligomers and proper (re)folding. The endoplasmic reticulum (ER) is an organelle that serves as the staging ground for the chaperone activities of protein transport, folding, and maturation in the early secretory pathway. We have developed a computational model to investigate potential mechanisms that enable multiple ER-resident molecules working in concert to effectively fold peptides and transport nascent proteins across the ER membrane. Although previous models focused on chaperone interactions with peptides, we have explored the influence of cooperativity among chaperone molecules to assist in protein folding and maturation. We found that chaperone cooperation led to a higher yield of folded molecules compared to when chaperones bound to peptides in a 1∶1 stoichiometry. We have concluded that the clustering or multiple binding of chaperones may facilitate protein folding in vivo.
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影响因子：
3.4
作者：
Chauwin, JF;Oster, G;Glick, BS
通讯作者：
Glick, BS
DOI：
10.1126/science.1178535
发表时间：
2009-12-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Becker T;Bhushan S;Jarasch A;Armache JP;Funes S;Jossinet F;Gumbart J;Mielke T;Berninghausen O;Schulten K;Westhof E;Gilmore R;Mandon EC;Beckmann R
通讯作者：
Beckmann R
影响因子：
3.4
作者：
Elston, TC
通讯作者：
Elston, TC
DOI：
10.1083/jcb.137.7.1483
发表时间：
1997-06-30
期刊：
The Journal of cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.4
作者：
Elston, TC
通讯作者：
Elston, TC