Molecular Biophysics Unit, Indian Institute of Science, Bangalore-560012, India.
Mol Biol Cell. 2021 Jul 1;32(14):1306-1319. doi: 10.1091/mbc.E20-12-0794. Epub 2021 May 12.
The neuronal dynamin1 functions in the release of synaptic vesicles by orchestrating the process of GTPase-dependent membrane fission. Dynamin1 associates with the plasma membrane-localized phosphatidylinositol-4,5-bisphosphate (PIP) through the centrally located pleckstrin homology domain (PHD). The PHD is dispensable as fission (in model membranes) can be managed, even when the PHD-PIP interaction is replaced by a generic polyhistidine- or polylysine-lipid interaction. However, the absence of the PHD renders a dramatic dampening of the rate of fission. These observations suggest that the PHD-PIP-containing membrane interaction could have evolved to expedite fission to fulfill the requirement of rapid kinetics of synaptic vesicle recycling. Here, we use a suite of multiscale modeling approaches to explore PHD-membrane interactions. Our results reveal that 1) the binding of PHD to PIP-containing membranes modulates the lipids toward fission-favoring conformations and softens the membrane, and 2) PHD associates with membrane in multiple orientations using variable loops as pivots. We identify a new loop (VL4), which acts as an auxiliary pivot and modulates the orientation flexibility of PHD on the membrane-a mechanism that we believe may be important for high-fidelity dynamin collar assembly. Together, these insights provide a molecular-level understanding of the catalytic role of PHD in dynamin-mediated membrane fission.
神经元中的 dynamin1 通过协调 GTPase 依赖性膜分裂过程来发挥突触小泡释放的作用。dynamin1 通过中央位于的 pleckstrin 同源结构域（PHD）与质膜定位的磷脂酰肌醇-4,5-二磷酸（PIP）结合。即使 PHD-PIP 相互作用被通用的多组氨酸或多赖氨酸脂质相互作用取代，分裂（在模型膜中）也可以进行，因此 PHD 是可有可无的。然而，PHD 的缺失会显著降低分裂的速度。这些观察结果表明，PHD-PIP 包含的膜相互作用可能已经进化，以加速分裂，以满足突触小泡回收的快速动力学要求。在这里，我们使用一系列多尺度建模方法来探索 PHD-膜相互作用。我们的结果表明：1）PHD 与含有 PIP 的膜结合会调节脂质以利于分裂的构象，并使膜变软；2）PHD 利用可变环作为枢轴，以多种方向与膜结合。我们确定了一个新的环（VL4），它作为辅助枢轴，调节 PHD 在膜上的取向灵活性——我们认为这种机制对于高保真 dynamin 套环组装可能很重要。总之，这些发现为 PHD 在 dynamin 介导的膜分裂中的催化作用提供了分子水平的理解。
