The HHMI Summer Institute, Marine Biological Laboratory, Woods Hole, MA 02543, USA.
Department of Biophysics and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Science. 2019 Mar 8;363(6431):1093-1097. doi: 10.1126/science.aau6313.
Biomolecular condensates concentrate macromolecules into foci without a surrounding membrane. Many condensates appear to form through multivalent interactions that drive liquid-liquid phase separation (LLPS). LLPS increases the specific activity of actin regulatory proteins toward actin assembly by the Arp2/3 complex. We show that this increase occurs because LLPS of the Nephrin-Nck-N-WASP signaling pathway on lipid bilayers increases membrane dwell time of N-WASP and Arp2/3 complex, consequently increasing actin assembly. Dwell time varies with relative stoichiometry of the signaling proteins in the phase-separated clusters, rendering N-WASP and Arp2/3 activity stoichiometry dependent. This mechanism of controlling protein activity is enabled by the stoichiometrically undefined nature of biomolecular condensates. Such regulation should be a general feature of signaling systems that assemble through multivalent interactions and drive nonequilibrium outputs.
生物分子凝聚物将大分子浓缩成焦点，而无需周围的膜。许多凝聚物似乎通过多价相互作用形成，从而驱动液-液相分离（LLPS）。LLPS 通过 Arp2/3 复合物增加了肌动蛋白调节蛋白对肌动蛋白组装的比活性。我们表明，这种增加是因为 Nephrin-Nck-N-WASP 信号通路在脂质双层上的 LLPS 增加了 N-WASP 和 Arp2/3 复合物在膜上的停留时间，从而增加了肌动蛋白的组装。停留时间随相分离簇中信号蛋白的相对化学计量而变化，从而使 N-WASP 和 Arp2/3 活性的化学计量依赖性。这种控制蛋白质活性的机制是由生物分子凝聚物的化学计量不确定性质所允许的。这种调节应该是通过多价相互作用组装并驱动非平衡输出的信号系统的一般特征。
