Cep57 regulates human centrosomes through multivalent interactions

• 成果类型: Article
• 署名作者: Yeh, Hung-Wei; Chen, Po-Pang; Yeh, Tzu-Chen; Lin, Shiou-Lan; Chen, Yue-Ting; Lin, Wan-Ping; Chen, Ting; Pang, Jia Meng; Lin, Kai-Ti; Wang, Lily Hui-Ching; Lin, Yu-Chun; Shih, Orion; Jeng, U-Ser; Hsia, Kuo-Chiang; Cheng, Hui-Chun
• 署名单位: National Tsing Hua University; National Tsing Hua University; National Tsing Hua University; National Tsing Hua University; National Synchrotron Radiation Research Center; National Tsing Hua University; Academia Sinica - Taiwan
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15157
• DOI: 10.1073/pnas.2305260121
• 发表日期: 2024-06-18
• 关键词: mosaic variegated aneuploidy; ray-scattering beamline; pericentriolar material; mitotic centrosome; microtubule; protein; mutations; reveals; phosphorylation; performance

摘要

Human Cep57 is a coiled- coil scaffold at the pericentriolar matrix (PCM), controlling centriole duplication and centrosome maturation for faithful cell division. Genetic truncation mutations of Cep57 are associated with the mosaic- variegated aneuploidy (MVA) syndrome. During interphase, Cep57 forms a complex with Cep63 and Cep152, serving as regulators for centrosome maturation. However, the molecular interplay of Cep57 with these essential scaffolding proteins remains unclear. Here, we demonstrate that Cep57 undergoes liquid-liquid phase separation (LLPS) driven by three critical domains (NTD, CTD, and polybasic LMN). In vitro Cep57 condensates catalyze microtubule nucleation via the LMN motif- mediated tubulin concentration. In cells, the LMN motif is required for centrosomal microtubule aster formation. Moreover, Cep63 restricts Cep57 assembly, expansion, and microtubule polymerization activity. Overexpression of competitive constructs for multivalent interactions, including an MVA mutation, leads to excessive centrosome duplication. In Cep57- depleted cells, self- assembly mutants failed to rescue centriole disengagement and PCM disorganization. Thus, Cep57's multivalent interactions are pivotal for maintaining the accurate structural and functional integrity of human centrosomes.