Scholl Daniel, Boyd Tumara, Latham Andrew P, Salazar Alexandra, Khan Asma, Boeynaems Steven, Holehouse Alex S, Lander Gabriel C, Sali Andrej, Park Donghyun, Deniz Ashok A, Lasker Keren
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
Quantitative Biosciences Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
bioRxiv. 2024 Dec 27:2024.12.27.630454. doi: 10.1101/2024.12.27.630454.
Biomolecular condensates play key roles in the spatiotemporal regulation of cellular processes. Yet, the relationship between atomic features and condensate function remains poorly understood. We studied this relationship using the polar organizing protein Z (PopZ) as a model system, revealing how its material properties and cellular function depend on its ultrastructure. We revealed PopZ's hierarchical assembly into a filamentous condensate by integrating cryo-electron tomography, biochemistry, single-molecule techniques, and molecular dynamics simulations. The helical domain drives filamentation and condensation, while the disordered domain inhibits them. Phase-dependent conformational changes prevent interfilament contacts in the dilute phase and expose client binding sites in the dense phase. These findings establish a multiscale framework that links molecular interactions and condensate ultrastructure to macroscopic material properties that drive cellular function.
生物分子凝聚物在细胞过程的时空调节中发挥着关键作用。然而，原子特征与凝聚物功能之间的关系仍知之甚少。我们以极性组织蛋白Z（PopZ）为模型系统研究了这种关系，揭示了其物质特性和细胞功能如何依赖于其超微结构。通过整合冷冻电子断层扫描、生物化学、单分子技术和分子动力学模拟，我们揭示了PopZ分级组装成丝状凝聚物的过程。螺旋结构域驱动丝化和凝聚，而无序结构域则抑制它们。相依赖的构象变化在稀相中阻止丝间接触，并在浓相中暴露客户结合位点。这些发现建立了一个多尺度框架，将分子相互作用和凝聚物超微结构与驱动细胞功能的宏观物质特性联系起来。
