VIB Center for Biology of Disease, KULeuven, 3000 Leuven, Belgium; Center for Human Genetics and Leuven Institute for Neuroscience and Disease (LIND), KULeuven, 3000 Leuven, Belgium.
Neuron. 2013 Sep 18;79(6):1169-82. doi: 10.1016/j.neuron.2013.06.039.
The CYFIP1/SRA1 gene is located in a chromosomal region linked to various neurological disorders, including intellectual disability, autism, and schizophrenia. CYFIP1 plays a dual role in two apparently unrelated processes, inhibiting local protein synthesis and favoring actin remodeling. Here, we show that brain-derived neurotrophic factor (BDNF)-driven synaptic signaling releases CYFIP1 from the translational inhibitory complex, triggering translation of target mRNAs and shifting CYFIP1 into the WAVE regulatory complex. Active Rac1 alters the CYFIP1 conformation, as demonstrated by intramolecular FRET, and is key in changing the equilibrium of the two complexes. CYFIP1 thus orchestrates the two molecular cascades, protein translation and actin polymerization, each of which is necessary for correct spine morphology in neurons. The CYFIP1 interactome reveals many interactors associated with brain disorders, opening new perspectives to define regulatory pathways shared by neurological disabilities characterized by spine dysmorphogenesis.
CYFIP1/SRA1 基因位于与多种神经发育障碍相关的染色体区域，包括智力障碍、自闭症和精神分裂症。CYFIP1 在两种明显不相关的过程中发挥双重作用，抑制局部蛋白质合成并促进肌动蛋白重塑。在这里，我们表明脑源性神经营养因子 (BDNF) 驱动的突触信号会将 CYFIP1 从翻译抑制复合物中释放出来，触发靶 mRNA 的翻译，并将 CYFIP1 转移到 WAVE 调节复合物中。活性 Rac1 通过分子内 FRET 改变 CYFIP1 的构象，这是改变两个复合物平衡的关键。因此，CYFIP1 协调了两种分子级联反应，即蛋白质翻译和肌动蛋白聚合，这两者对于神经元中正确的棘突形态都是必需的。CYFIP1 的相互作用组揭示了许多与脑部疾病相关的相互作用因子，为定义以棘突发育不良为特征的神经发育障碍的共享调节途径开辟了新的视角。
