蛋白質(zhì)折疊問題是分子生物學(xué)中心法則尚未解決的一個重大生物學(xué)問題。近日,，德國科學(xué)家實(shí)驗(yàn)發(fā)現(xiàn),，蛋白質(zhì)折疊過程中分子伴侶亞基能夠增強(qiáng)異構(gòu)酶的活性,，兩者功能的聯(lián)合產(chǎn)生了高效的蛋白質(zhì)折疊輔助作用。相關(guān)研究成果發(fā)表在近期的《美國國家科學(xué)院院刊》上,。
氨基酸鏈必須折疊成特定的空間結(jié)構(gòu),，蛋白質(zhì)才具有生物學(xué)功能,。當(dāng)一種蛋白質(zhì)沒有正確地折疊時，會導(dǎo)致很多種疾病,，例如鐮刀型細(xì)胞貧血癥,、瘋牛病和老年癡呆癥等。因此,，蛋白質(zhì)折疊問題也是生命科學(xué)領(lǐng)域的前沿課題之一,，與人類健康密切相關(guān)。
近年來的研究表明,，特定的異構(gòu)酶有促進(jìn)蛋白質(zhì)折疊的功能,。其原因在于連接氨基酸的肽鍵有順式和反式兩種異構(gòu)體，順式肽鍵允許形成細(xì)長的肽鏈,，反式肽鍵則導(dǎo)致肽鏈的扭結(jié),，特定的異構(gòu)酶可促進(jìn)上述順反兩種異構(gòu)體之間的轉(zhuǎn)換。如果缺少所需的異構(gòu)酶,，這個轉(zhuǎn)換的過程就會非常緩慢,。另一類有折疊輔助作用的是分子伴侶，它可識別肽鏈的非天然構(gòu)象并與之結(jié)合,，防止錯誤折疊或產(chǎn)生不溶物,，完成功能后與之分離,，不構(gòu)成這些蛋白質(zhì)執(zhí)行功能時的組分,。不過，上述兩種輔助折疊功能協(xié)同合作的機(jī)理一直不清楚,。
德國拜羅伊特大學(xué)和馬克斯—普朗克蛋白質(zhì)折疊酶學(xué)研究站科學(xué)家的最新研究表明,，在輔助折疊蛋白鏈時,，有分子伴侶亞基的幫助，脯氨酸異構(gòu)酶對不同的氨基酸都能起到同樣好的效果,?？茖W(xué)家描述了一種機(jī)制來說明這些酶是如何使用它們的亞基來作為最佳折疊酶工作的。首先,，分子伴侶的亞基俘獲那些尚未折疊的肽鏈,，然后把它們交給異構(gòu)酶的亞基。這個很快就完成的傳遞過程簡化了異構(gòu)酶亞基的工作,。異構(gòu)酶的工作速度很可能取決于這兩個功能中心的傳遞情況,。
上述結(jié)論是科學(xué)家通過比較兩種不同的酶得出的，一種酶僅擁有脯氨酸異構(gòu)酶亞基,，另一種除了催化亞基外還擁有伴侶分子亞基,。在沒有分子伴侶亞基的情況下，異構(gòu)酶活性高度依賴于脯氨酸序列周圍相對應(yīng)的短肽和待折疊的蛋白鏈。而有了分子伴侶亞基的存在,，蛋白質(zhì)折疊的活動大幅度增加,，且獨(dú)立于氨基酸的化學(xué)性質(zhì)。未折疊的蛋白鏈與分子伴侶的良好結(jié)合可確保其很好的折疊,，并且可用與序列無關(guān)的折疊酶來加速,。（生物谷Bioon.com）
生物谷推薦原始出處：
PNAS November 17, 2009, doi: 10.1073/pnas.0909544106
Chaperone domains convert prolyl isomerases into generic catalysts of protein folding
Roman P. Jakoba, Gabriel Zoldáka, Tobias Aumüllerb and Franz X. Schmida,1
aLaboratorium für Biochemie und Bayreuther Zentrum für Molekulare Biowissenschaften, Universit?t Bayreuth, D-95440 Bayreuth, Germany; and
bMax Planck Research Unit for Enzymology of Protein Folding, D-06120 Halle/Saale, Germany
The cis/trans isomerization of peptide bonds before proline (prolyl bonds) is a rate-limiting step in many protein folding reactions, and it is used to switch between alternate functional states of folded proteins. Several prolyl isomerases of the FK506-binding protein family, such as trigger factor, SlyD, and FkpA, contain chaperone domains and are assumed to assist protein folding in vivo. The prolyl isomerase activity of FK506-binding proteins strongly depends on the nature of residue Xaa of the Xaa-Pro bond. We confirmed this in assays with a library of tetrapeptides in which position Xaa was occupied by all 20 aa. A high sequence specificity seems inconsistent with a generic function of prolyl isomerases in protein folding. Accordingly, we constructed a library of protein variants with all 20 aa at position Xaa before a rate-limiting cis proline and used it to investigate the performance of trigger factor and SlyD as catalysts of proline-limited folding. The efficiencies of both prolyl isomerases were higher than in the tetrapeptide assays, and, intriguingly, this high activity was almost independent of the nature of the residue before the proline. Apparently, the almost indiscriminate binding of the chaperone domain to the refolding protein chain overrides the inherently high sequence specificity of the prolyl isomerase site. The catalytic performance of these folding enzymes is thus determined by generic substrate recognition at the chaperone domain and efficient transfer to the active site in the prolyl isomerase domain.
