Institut de Génétique et de Biologie Moléculaire et cellulaire (IGBMC), Centre National de Recherche scientifique (CNRS) UMR 7104 - Institut National de santé et de Recherche Médicale (Inserm) U964 - Université de Strasbourg, 1 rue Laurent Fries, Illkirch, France.
Department of Structural Cell Biology, Max Planck Institute of Biochemistry, Am Klopferspitz 18, Martinsried, Munich, Germany.
Cell Rep. 2023 Jan 31;42(1):111902. doi: 10.1016/j.celrep.2022.111902. Epub 2022 Dec 30.
The evolutionary conserved CCR4-NOT complex functions in the cytoplasm as the main mRNA deadenylase in both constitutive mRNA turnover and regulated mRNA decay pathways. The versatility of this complex is underpinned by its modular multi-subunit organization, with distinct structural modules actuating different functions. The structure and function of all modules are known, except for that of the N-terminal module. Using different structural approaches, we obtained high-resolution data revealing the architecture of the human N-terminal module composed of CNOT1, CNOT10, and CNOT11. The structure shows how two helical domains of CNOT1 sandwich CNOT10 and CNOT11, leaving the most conserved domain of CNOT11 protruding into solvent as an antenna. We discovered that GGNBP2, a protein identified as a tumor suppressor and spermatogenic factor, is a conserved interacting partner of the CNOT11 antenna domain. Structural and biochemical analyses thus pinpoint the N-terminal CNOT1-CNOT10-CNOT11 module as a conserved protein-protein interaction platform.
进化保守的 CCR4-NOT 复合物在细胞质中作为主要的 mRNA 脱腺苷酸化酶，参与组成型 mRNA 周转和调控的 mRNA 衰减途径。该复合物的多功能性源于其模块化的多亚基组织，不同的结构模块执行不同的功能。除了 N 端模块外，所有模块的结构和功能都已为人所知。我们使用不同的结构方法，获得了高分辨率的数据，揭示了由 CNOT1、CNOT10 和 CNOT11 组成的人源 N 端模块的结构。该结构展示了 CNOT1 的两个螺旋结构域如何夹在 CNOT10 和 CNOT11 之间，使 CNOT11 中最保守的结构域突出到溶剂中作为一个天线。我们发现，GGNBP2 是一种被鉴定为肿瘤抑制因子和精子发生因子的蛋白质，是 CNOT11 天线结构域的保守相互作用伙伴。因此，结构和生化分析将 N 端 CNOT1-CNOT10-CNOT11 模块确定为一个保守的蛋白-蛋白相互作用平台。
