美国《生物化学杂志》7月刊发了上海生命科学研究院生物化学与细胞生物学研究所胡红雨组与上海药物所林东海组合作完成的研究论文，研究人员用核磁共振解析了一个新的泛素结合结构域（简称为PFUC）的溶液结构，并探讨了它与泛素识别的特异性及分子机制。
泛素蛋白酶体是细胞内蛋白质质量控制系统的重要组成部分。大部分Lys48连接的泛素链所修饰的蛋白质将被运送到蛋白酶体进行降解，在此过程中泛素结合结构域对于底物的识别和运送起了关键作用。
已有一些泛素结合结构域（如UBA、UIM、CUE等）被陆续研究和报道。内质网相关的蛋白质降解（ERAD）在细胞中分泌蛋白和膜蛋白的质量控制中起了重要作用。人的磷脂酶A2激活蛋白（PLAA）可能参与ERAD的过程，然而其分子机制还不清楚。PLAA与ERAD的核心分子P97/VCP的相互作用是其参与ERAD的重要证据。胡红雨组傅青山等人的工作分析了PLAA的中间区域（PFU或UIM）参与泛素化底物运送的调节作用，从中找到了结构相对完整的结构域PFUC（PFU core domain）。通过解析PFUC的溶液结构，发现它具有新的折叠模式，且在溶液中具有脯氨酸顺反异构体，并且它与泛素的结合受到其溶液动力学性质的影响。
该论文提出了一种新的泛素结合模式，为进一步研究真核细胞蛋白质的降解提供了结构基础。PLAA识别泛素可能是其发挥其生物学功能的核心事件，这些过程都与泛素的识别密切相关。因此，研究PLAA识别泛素的机制对于认识其在ERAD或其他信号通路中的功能具有重要意义。
该项研究工作得到了国家科技部、基金委 、中国科学院的经费支持。（生物谷Bioon.com）
生物谷推荐原始出处：
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.
