S-nitrosylation of cyclin-dependent kinase 5 (cdk5) regulates its kinase activity and dendrite growth during neuronal development.
Precise regulation of cyclin-dependent kinase 5 (Cdk5), a member of the cyclin-dependent kinase family, is critical for proper neuronal development and functions. Cdk5 is activated through its association with the neuron-specific activator p35 or p39. Nonetheless, how its kinase activity is regulated in neurons is not well understood. In this study, we found that Cdk5 activity is regulated by S-nitrosylation, a post-translational modification of protein that affects a plethora of neuronal functions. S-nitrosylation of Cdk5 occurs at Cys83, which is one of the critical amino acids within the ATP-binding pocket of the kinase. Upon S-nitrosylation, Cdk5 exhibits reduced kinase activity, whereas mutation of Cys83 to Ala on Cdk5 renders the kinase refractory to such inhibition. Importantly, S-nitrosylated Cdk5 can be detected in the mouse brain, and blocking the S-nitrosylation of Cdk5 in cultured hippocampal neurons enhances dendritic growth and branching. Together, our findings reveal an important role of S-nitrosylation in regulating Cdk5 kinase activity and dendrite growth in neurons during development.
Zhang
Peng
P
Department of Biochemistry, Molecular Neuroscience Center and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.
Yu
Pei-Chun
PC
Tsang
Anthony H K
AH
Chen
Yu
Y
Fu
Amy K Y
AK
Fu
Wing-Yu
WY
Chung
Kenny K
KK
Ip
Nancy Y
NY
D000818:Animals; D001710:Biotin; D001923:Brain Chemistry / Q000502:physiology; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics* / Q000502:physiology*; D003545:Cysteine / Q000502:physiology; D018076:DNA, Complementary / Q000235:genetics; D003712:Dendrites / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology / Q000254:growth & development; D006801:Humans; D051379:Mice; D009474:Neurons / Q000502:physiology*; D009603:Nitroso Compounds / Q000737:chemistry; D011499:Protein Processing, Post-Translational / Q000235:genetics* / Q000502:physiology*; D011993:Recombinant Fusion Proteins; D014162:Transfection
D018076:DNA, Complementary; D009603:Nitroso Compounds; D011993:Recombinant Fusion Proteins; D001710:Biotin; D051360:Cyclin-Dependent Kinase 5; D003545:Cysteine