Department of Biochemistry and Molecular Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
Department of Immunology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular and Molecular Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
Mol Cell. 2021 Aug 19;81(16):3262-3274.e3. doi: 10.1016/j.molcel.2021.06.010. Epub 2021 Jul 1.
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 α-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.
N 肽段途径是一组靶向蛋白酶体降解底物 N 端不稳定残基的蛋白水解系统。最近，甘氨酸/N 肽段途径被确定为 N 肽段途径的一个新分支。N 端甘氨酸肽段（Gly/N-degron）被 Cullin 2-RING E3 泛素连接酶（CRL2）的底物受体 ZYG11B 和 ZER1 识别。本文呈现了与各种 Gly/N-degrons 结合的 ZYG11B 和 ZER1 的晶体结构。这些结构表明，ZYG11B 和 ZER1 利用其装甲重复序列形成一个深而窄的腔，主要与 Gly/N-degrons 的前四个残基结合。Gly/N-degron 的α-氨基通过五个保守氢键容纳在酸性口袋中。这些结构，以及生化研究，阐明了 ZYG11B 和 ZER1 对 Gly/N-degron 特异性识别的分子基础，为未来基于结构的化学探针设计提供了关键信息。
