JAMM: a metalloprotease-like zinc site in the proteasome and signalosome.
JAMM: a metalloprotease-like zinc site in the proteasome and signalosome.
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DOI：
10.1371/journal.pbio.0020002
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发表时间：
2004-01
期刊：
影响因子：
9.8
通讯作者：
Deshaies RJ
中科院分区：
文献类型：
--
作者：
Ambroggio XI;Rees DC;Deshaies RJ
Rpn 11和Csn 5中的JAMM（JAB 1/MPN/Mov 34金属酶）基序分别是蛋白酶体和信号体固有的异肽酶活性的基础。我们在这里表明，古细菌蛋白AfJAMM具有锌金属蛋白酶的关键特征，但具有独特的折叠。保守的EXnHS/THX 7SXXD基序的组氨酸和天冬氨酸与锌配位，而谷氨酸与水配体氢键结合。通过类比嗜热菌蛋白酶的活性位点，我们预测，谷氨酸作为酸碱催化剂和第二丝氨酸稳定四面体中间体。Csn 5的诱变证实了这些残基是Nedd 8异肽酶活性所需的。由JAMM基序指定的活性位点样结构激发了基于结构的方法来研究JAMM结构域蛋白以及开发治疗性蛋白酶体和信号体抑制剂。蛋白质结构研究表明，蛋白酶体中的去泛素化是由具有锌金属蛋白酶特征的蛋白质进行的
The JAMM (JAB1/MPN/Mov34 metalloenzyme) motif in Rpn11 and Csn5 underlies isopeptidase activities intrinsic to the proteasome and signalosome, respectively. We show here that the archaebacterial protein AfJAMM possesses the key features of a zinc metalloprotease, yet with a distinct fold. The histidine and aspartic acid of the conserved EXnHS/THX7SXXD motif coordinate a zinc, whereas the glutamic acid hydrogen-bonds an aqua ligand. By analogy to the active site of thermolysin, we predict that the glutamic acid serves as an acid-base catalyst and the second serine stabilizes a tetrahedral intermediate. Mutagenesis of Csn5 confirms these residues are required for Nedd8 isopeptidase activity. The active site-like architecture specified by the JAMM motif motivates structure-based approaches to the study of JAMM domain proteins and the development of therapeutic proteasome and signalosome inhibitors. Protein structure studies suggest that deubiquitination in the proteasome is carried out by a protein with features of a zinc metalloprotease