Molecular recognition of p53 and MDM2 by USP7/HAUSP
Molecular recognition of p53 and MDM2 by USP7/HAUSP
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DOI：
10.1038/nsmb1067
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发表时间：
2006-03-01
影响因子：
16.8
通讯作者：
Frappier, L
中科院分区：
文献类型：
--
作者：
Sheng, Y;Saridakis, V;Frappier, L
泛素特异性蛋白酶USP 7在p53通路中具有关键作用，从而稳定p53和MDM 2。我们发现USP 7的N-末端结构域结合p53和MDM 2中两个紧密间隔的4-残基位点，落在p53残基359-367和MDM 2残基147-159之间。用USP 7测定两种p53肽和一种MDM 2肽的共晶体结构。这些肽与Epstein-Barr核抗原-1结合USP 7的相同表面，解释了相互作用的竞争性质。结构和诱变数据表明结合USP 7的肽中P/AXXS基序的偏好。由丝氨酸形成的接触对于所有肽都是相同的和至关重要的，并且USP 7的肽结合口袋中的Trp 165也是至关重要的。这些结果有助于阐明USP 7的底物识别机制和p53通路的调节。
The ubiquitin-specific protease, USP7, has key roles in the p53 pathway whereby it stabilizes both p53 and MDM2. We show that the N-terminal domain of USP7 binds two closely spaced 4-residue sites in both p53 and MDM2, falling between p53 residues 359-367 and MDM2 residues 147-159. Cocrystal structures with USP7 were determined for both p53 peptides and for one MDM2 peptide. These peptides bind the same surface of USP7 as Epstein-Barr nuclear antigen-1, explaining the competitive nature of the interactions. The structures and mutagenesis data indicate a preference for a P/AXXS motif in peptides that bind USP7. Contacts made by serine are identical and crucial for all peptides, and Trp165 in the peptide-binding pocket of USP7 is also crucial. These results help to elucidate the mechanism of substrate recognition by USP7 and the regulation of the p53 pathway.