Molecular modeling of BAD complex resided in a mitochondrion integrating glycolysis and apoptosis.
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.
Yang
Jie
J
State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing 210093, PR China. yangjie@nju.edu.cn
Li
Jia-Huang
JH
Wang
Jin
J
Zhang
Chen-Yu
CY
D000595:Amino Acid Sequence; D017209:Apoptosis / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D005941:Glucokinase / Q000235:genetics / Q000378:metabolism; D006019:Glycolysis / Q000502:physiology; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000378:metabolism; D010766:Phosphorylation; D054645:Protein Phosphatase 1 / Q000378:metabolism; D016415:Sequence Alignment; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000235:genetics / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
C494819:BAD protein, human; C494811:BCL2L1 protein, human; D046912:Multiprotein Complexes; C114864:WASF1 protein, human; D051300:Wiskott-Aldrich Syndrome Protein Family; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D005941:Glucokinase; D017868:Cyclic AMP-Dependent Protein Kinases; D054645:Protein Phosphatase 1