美國(guó)《生物化學(xué)雜志》7月刊發(fā)了上海生命科學(xué)研究院生物化學(xué)與細(xì)胞生物學(xué)研究所胡紅雨組與上海藥物所林東海組合作完成的研究論文,，研究人員用核磁共振解析了一個(gè)新的泛素結(jié)合結(jié)構(gòu)域（簡(jiǎn)稱(chēng)為PFUC）的溶液結(jié)構(gòu)，并探討了它與泛素識(shí)別的特異性及分子機(jī)制,。
泛素蛋白酶體是細(xì)胞內(nèi)蛋白質(zhì)質(zhì)量控制系統(tǒng)的重要組成部分,。大部分Lys48連接的泛素鏈所修飾的蛋白質(zhì)將被運(yùn)送到蛋白酶體進(jìn)行降解,，在此過(guò)程中泛素結(jié)合結(jié)構(gòu)域?qū)τ诘孜锏淖R(shí)別和運(yùn)送起了關(guān)鍵作用。
已有一些泛素結(jié)合結(jié)構(gòu)域（如UBA,、UIM,、CUE等）被陸續(xù)研究和報(bào)道。內(nèi)質(zhì)網(wǎng)相關(guān)的蛋白質(zhì)降解（ERAD）在細(xì)胞中分泌蛋白和膜蛋白的質(zhì)量控制中起了重要作用,。人的磷脂酶A2激活蛋白（PLAA）可能參與ERAD的過(guò)程,，然而其分子機(jī)制還不清楚。PLAA與ERAD的核心分子P97/VCP的相互作用是其參與ERAD的重要證據(jù),。胡紅雨組傅青山等人的工作分析了PLAA的中間區(qū)域（PFU或UIM）參與泛素化底物運(yùn)送的調(diào)節(jié)作用,，從中找到了結(jié)構(gòu)相對(duì)完整的結(jié)構(gòu)域PFUC（PFU core domain）。通過(guò)解析PFUC的溶液結(jié)構(gòu),，發(fā)現(xiàn)它具有新的折疊模式,，且在溶液中具有脯氨酸順?lè)串悩?gòu)體，并且它與泛素的結(jié)合受到其溶液動(dòng)力學(xué)性質(zhì)的影響,。
該論文提出了一種新的泛素結(jié)合模式,，為進(jìn)一步研究真核細(xì)胞蛋白質(zhì)的降解提供了結(jié)構(gòu)基礎(chǔ)。PLAA識(shí)別泛素可能是其發(fā)揮其生物學(xué)功能的核心事件,，這些過(guò)程都與泛素的識(shí)別密切相關(guān),。因此，研究PLAA識(shí)別泛素的機(jī)制對(duì)于認(rèn)識(shí)其在ERAD或其他信號(hào)通路中的功能具有重要意義,。
該項(xiàng)研究工作得到了國(guó)家科技部,、基金委 、中國(guó)科學(xué)院的經(jīng)費(fèi)支持,。（生物谷Bioon.com）
生物谷推薦原始出處：
J. Biol. Chem., Vol. 284, Issue 28, 19043-19052, July 10, 2009
Structural Basis for Ubiquitin Recognition by a Novel Domain from Human Phospholipase A2-activating Protein*
Qing-Shan Fu, Chen-Jie Zhou, Hong-Chang Gao?, Ya-Jun Jiang, Zi-Ren Zhou, Jing Hong?, Wen-Ming Yao?, Ai-Xin Song, Dong-Hai Lin?1, and Hong-Yu Hu2
From the From the State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, , the ?Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, and , the Graduate School of the Chinese Academy of Sciences, Beijing 100039, China
ABSTRACT
Ubiquitin (Ub) is an essential modifier conserved in all eukaryotes from yeast to human. Phospholipase A2-activating protein (PLAA), a mammalian homolog of yeast DOA1/UFD3, has been proposed to be able to bind with Ub, which plays important roles in endoplasmic reticulum-associated degradation, vesicle formation, and DNA damage response. We have identified a core domain from the PLAA family ubiquitin-binding region of human PLAA (residues 386–465, namely PFUC) that can bind Ub and elucidated its solution structure and Ub-binding mode by NMR approaches. The PFUC domain possesses equal population of two conformers in solution by cis/trans-isomerization, whereas the two isomers exhibit almost equivalent Ub binding abilities. This domain structure takes a novel fold consisting of four β-strands and two -helices, and the Ub-binding site on PFUC locates in the surface of 2-helix, which is to some extent analogous to those of UBA, CUE, and UIM domains. This study provides structural basis and biochemical information for Ub recognition of the novel PFU domain from a PLAA family protein that may connect ubiquitination and degradation in endoplasmic reticulum-associated degradation.
