近日,，刊登在國際著名雜志PNAS上的一篇報道指出,，在雙精氨酸分泌系統(tǒng)（TAT）中發(fā)現(xiàn)了質(zhì)量控制的機制，雙精氨酸分泌系統(tǒng)是植物,、細菌和古細菌的一種蛋白質(zhì)輸出途徑,。這種跨膜的蛋白質(zhì)運輸是一種基本的生命過程，理解TAT途徑如何工作對于理解細菌如何產(chǎn)生對抗生素耐藥非常重要,。
TAT途徑非常值得注意,，不像其它過程，TAT過程中,，蛋白質(zhì)是以緊密折疊的形式經(jīng)過細胞膜的,。這種途徑允許蛋白質(zhì)合適地折疊，錯誤折疊將不會被允許通過,。在TAT出口中使用遺傳選擇的方法,，研究者就可以分離出一種突變（TAT機器中的抑制子），來使得細菌即便輸出錯誤蛋白的時候也使得細菌存活,。細菌的這種能力歸咎于他們外排錯誤折疊蛋白的能力,。正常細菌是不行的。研究者提出了TAT機器直接調(diào)節(jié)蛋白質(zhì)輸出的證據(jù),。
他們推測,，TAT機器包含了一些組分可以感知是否蛋白質(zhì)被正確折疊,，并且區(qū)別蛋白石處于折疊還是未折疊的狀態(tài)。TAT途徑調(diào)節(jié)蛋白質(zhì)的質(zhì)量為生物技術(shù)公司開發(fā)合適的抗體提供了基礎(chǔ)條件,。數(shù)年前,，研究者Delisa關(guān)于TAT路徑的研究成果就為生物技術(shù)公司開發(fā)治療阿爾茲海默癥的藥物提供了思路。
所有這種機制,，包括質(zhì)量控制特征都是一種生物技術(shù)元素,，應(yīng)當被用于尋找抗體，使其特異性的結(jié)合至其靶點上,。相關(guān)研究由國立衛(wèi)生研究院支持,。（生物谷Bioon.com）
編譯自：Quality-control mechanism found in bacteria
doi:10.1073/pnas.1210140109
PMC:
PMID:
Twin-arginine translocase mutations that suppress folding quality control and permit export of misfolded substrate proteins
Mark A. Roccoa, Dujduan Waraho-Zhmayevb,c, and Matthew P. DeLisaa,b,1
The bacterial twin-arginine translocation (Tat) pathway facilitates the transport of correctly folded proteins across the tightly sealed cytoplasmic membrane. Here, we report the isolation and characterization of suppressor mutations in the Tat translocase that allow export of misfolded proteins, which form structures that are not normally tolerated by the wild-type translocase. Selection of suppressors was enabled by a genetic assay that effectively linked in vivo folding and stability of a test protein with Tat export efficiency of a selectable marker protein, namely TEM-1 β-lactamase. By using a test protein named α3B—a designed three-helix-bundle protein that forms collapsed, stable molten globules but lacks a uniquely folded structure—translocase mutants that rescued export of this protein were readily identified. Each mutant translocase still efficiently exported folded substrate proteins, indicating that the substrate specificity of suppressors was relaxed but not strictly altered. A subset of the suppressors could also export other misfolded proteins, such as the aggregation-prone α3A protein and reduced alkaline phosphatase. Importantly, the isolation of genetic suppressors that inactivate the Tat quality-control mechanism provides direct evidence for the participation of the Tat translocase in structural proofreading of substrate proteins and reveals epitopes in the translocase that are important for this process.
