Molecular basis for recognitionof Gly/N-degrons by CRL2ZYG11B and CRL2ZER1
Molecular basis for recognitionof Gly/N-degrons by CRL2ZYG11B and CRL2ZER1
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CRL2(ZYG11B) 和 CRL2(ZER1) 识别 Gly/N-degron 的分子基础
DOI：
10.1016/j.molcel.2021.06.010
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发表时间：
2021-08-19
期刊：
影响因子：
16
通讯作者：
Dong, Cheng
中科院分区：
文献类型：
--
作者：
Yan, Xiaojie;Li, Yao;Dong, Cheng
n -降解途径是一组蛋白水解系统，其目标是蛋白酶体降解底物的n端不稳定残基。最近，Gly/N-degron通路被确定为N-degron通路的一个新分支。Cullin 2-RING E3泛素连接酶（CRL2）的底物受体ZYG11B和ZER1可以识别n端甘氨酸度子（Gly/N-degron）。在这里我们展示了ZYG11B和ZER1结合到不同的Gly/N-degrons的晶体结构。结构表明，ZYG11B和ZER1利用它们的armadillo （ARM）重复序列形成一个深而窄的腔，主要结合Gly/N-degrons的前四个残基。Gly/N-degron的a-氨基被五个保守的氢键安置在酸性口袋中。这些结构与生物化学研究一起，揭示了ZYG11B和ZER1特异性识别Gly/N-degron的分子基础，为未来基于结构的化学探针设计提供了关键信息。
N-degron pathways are a set of proteolytic systems that target the N-terminal destabilizing residues of substrates for proteasomal degradation. Recently, the Gly/N-degron pathway has been identified as a new branch of the N-degron pathway. The N-terminal glycine degron (Gly/N-degron) is recognized by ZYG11B and ZER1, the substrate receptors of the Cullin 2-RING E3 ubiquitin ligase (CRL2). Here we present the crystal structures of ZYG11B and ZER1 bound to various Gly/N-degrons. The structures reveal that ZYG11B and ZER1 utilize their armadillo (ARM) repeats forming a deep and narrow cavity to engage mainly the first four residues of Gly/N-degrons. The a-amino group of the Gly/N-degron is accommodated in an acidic pocket by five conserved hydrogen bonds. These structures, together with biochemical studies, decipher the molecular basis for the specific recognition of the Gly/N-degron by ZYG11B and ZER1, providing key information for future structure-based chemical probe design.