密歇根大學(xué)和霍華德休斯醫(yī)學(xué)研究所的科學(xué)家發(fā)現(xiàn)了一種命名為HdeA的蛋白質(zhì)分子伴侶,，這種蛋白質(zhì)分子伴侶能夠阻止大腸桿菌免受胃酸的干擾，并能防止蛋白質(zhì)形成破壞性的團(tuán)塊,。這篇研究報(bào)告發(fā)表在近期的Proceedings of the National Academy of Sciences雜志網(wǎng)絡(luò)版上,。
像大腸桿菌之類(lèi)的致病菌,，一旦被攝入到人體或動(dòng)物體內(nèi)并接觸到胃酸，將導(dǎo)致致病菌自身的蛋白質(zhì)處于非折疊狀態(tài),，這種非折疊狀態(tài)干擾蛋白質(zhì)正常功能,，如果此時(shí)蛋白質(zhì)伴侶HdeA沒(méi)有介入，將很快引起細(xì)菌死亡,。當(dāng)病原菌進(jìn)入胃中,，HdeA能夠與非折疊的蛋白質(zhì)緊密結(jié)合，通過(guò)結(jié)合到細(xì)菌的蛋白質(zhì)上,，伴侶分子能夠保護(hù)細(xì)菌免于死亡,。
該課題組發(fā)現(xiàn)，當(dāng)細(xì)菌進(jìn)入到小腸的堿性環(huán)境中,，HdeA釋放非折疊蛋白并使蛋白質(zhì)重新折疊成正確的構(gòu)象,，而不是聚集成團(tuán)。據(jù)主要研究人員Tim Tapley介紹,，因?yàn)橐坏┓钦郫B蛋白被HdeA同時(shí)釋放,，則很容易聚集起來(lái)，導(dǎo)致細(xì)菌死亡,，HdeA蛋白采用了一種獨(dú)特的“定時(shí)釋放”機(jī)制,。在該研究中，研究人員觀察到,，蛋白質(zhì)伴侶HdeA逐漸釋放非折疊蛋白,，這使其更傾向于重新折疊成正確構(gòu)象。
大多數(shù)分子伴侶在發(fā)揮功能時(shí)需要大量的細(xì)胞能量,，但HdeA能夠利用周?chē)h(huán)境中pH改變產(chǎn)生的能量,，如細(xì)菌胃中的酸性環(huán)境轉(zhuǎn)移到微堿性的小腸環(huán)境中,。（生物谷Bioon.com）
生物谷推薦原始出處：
PNAS March 24, 2009, doi: 10.1073/pnas.0811811106
Structural plasticity of an acid-activated chaperone allows promiscuous substrate binding
Timothy L. Tapleya,b, Jan L. K?rnera, Madhuri T. Bargea, Julia Hupfelda, Joseph A. Schauertec, Ari Gafnic, Ursula Jakoba and James C. A. Bardwella,b,1
aDepartment of Molecular, Cellular, and Developmental Biology,
cBiophysics Research Division and Department of Biological Chemistry, and
bHoward Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109
HdeA has been shown to prevent acid-induced aggregation of proteins. With a mass of only 9.7 kDa, HdeA is one of the smallest chaperones known. Unlike other molecular chaperones, which are typically complex, multimeric ATP-dependent machines, HdeA is known to undergo an acid-induced dimer to monomer transition and functions at low pH as a disordered monomer without the need for energy factors. Thus, HdeA must possess features that allow it to bind substrates and regulate substrate affinity in a small and energy-independent package. To understand better how HdeA accomplishes this, we studied the conformational changes that accompany a shift to low pH and substrate binding. We find that the acid-induced partial unfolding and monomerization that lead to HdeA activation occur very rapidly (k >3.5 s?1). Activation exposes the hydrophobic dimer interface, which we found to be critical for substrate binding. We show by intramolecular FRET that the partially unfolded character of active HdeA allows the chaperone to adopt different conformations as required for the recognition and high-affinity binding of different substrate proteins. These efficient adaptations help to explain how a very small protein is rapidly activated and can bind a broad range of substrate proteins in a purely pH-regulated manner.
