State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing 210093, PR China.
J Theor Biol. 2010 Sep 21;266(2):231-41. doi: 10.1016/j.jtbi.2010.06.009. Epub 2010 Jun 9.
BAD (Bcl-2 antagonist of cell death) and GK (glucokinase) reside in a mitochondrial complex together with PKA and PP1 catalytic units (PKAc and PP1c) and WAVE-1 that integrates glycolysis and apoptosis. Our research results reveal that BAD is phosphorylated and inactivated on Ser 75 in a BAD-Bcl-xL complex by PKA (targeted to mitochondria through association with WAVE1), resulting in the dissociation of BAD and its binding to GK. Moreover, GK can interact with PP1c and also distinguish WAVE1. On the other hand, BAD is dephosphorylated and activated on Ser75 by PP1c, leading to the separation of PKAc and its binding to the regulatory (R) subunit of PKA which by the dimerization domain of its R subunit connects with WAVE1 linked with GK of the complex. This may be the reason of the complex existing in liver mitochondria, regardless of phosphorylated and dephosphorylated BAD. Additionally, GK like PKA may also prevent Bcl-xL from rebinding to BAD by phosphorylating BAD at Ser 118. The BAD complex model reveals that BAD and GK play key roles because of BAD as a substrate for the PKA-PP1 pair and by BH3 domain directly interacting with GK. This is helpful for our development and research of the molecular mechanism of BAD integrating glycolysis and apoptosis.
BAD（细胞死亡的 Bcl-2 拮抗剂）和 GK（葡糖激酶）与 PKA 和 PP1 催化单元（PKAc 和 PP1c）以及整合糖酵解和细胞凋亡的 WAVE-1 一起存在于线粒体复合物中。我们的研究结果表明，BAD 在 BAD-Bcl-xL 复合物中通过 PKA（通过与 WAVE1 结合靶向线粒体）在 Ser 75 上磷酸化和失活，导致 BAD 与其与 GK 的结合解离。此外，GK 可以与 PP1c 相互作用，也可以区分 WAVE1。另一方面，BAD 在 Ser75 上被 PP1c 去磷酸化和激活，导致 PKAc 与其与 PKA 的调节（R）亚基的结合解离，其通过 R 亚基的二聚化结构域与与复合物中的 GK 相连的 WAVE1 相连。这可能是复合物存在于肝线粒体中的原因，而不管 BAD 是否磷酸化和去磷酸化。此外，GK 可能像 PKA 一样，通过在 Ser 118 处磷酸化 BAD，防止 Bcl-xL 重新与 BAD 结合。BAD 复合物模型表明，BAD 和 GK 发挥关键作用，因为 BAD 是 PKA-PP1 对的底物，并且 BH3 结构域直接与 GK 相互作用。这有助于我们开发和研究 BAD 整合糖酵解和细胞凋亡的分子机制。
