Author(s)

Zhiqiang Hou^1,2*, Lijing Su^1,3, Xiaoyan Liu⁴

¹Department of Biophysics, Dallas, USA.
²Center for Alzheimer and Neurodegenerative Disease, Dallas, USA.
³Center for the Genetics of Host Defense, Dallas, USA.
⁴Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, USA.

The protein family of 14-3-3(s) has risen to a position of higher importance as an adaptor protein in cell biology. The seven highly conserved human 14-3-3 proteins coordinate diverse cellular processes including apoptosis, DNA damage response, protein trafficking, and others. In liver hepatocytes, 14-3-3β binds to Ser¹⁹⁶-phosphorilated glucose-responsive carbohydrate response element-binding protein (ChREBP) to inhibit converting excess carbohydrate to fat by regulating the nuclear/cytosol trafficking of ChREBP. Here, we report X-ray crystal structures of homodimeric mammalian 14-3-3β in its apo, Malate-bound forms. The determined apo structure was captured with one monomer in the closed state, whereas the other one had an open conformation. Strikingly, 14-3-3β binds Malate dynamically with a double-closed state, which is distinct from all previously characterized 14-3-3(s) and target ligand-binding modes. Malate docks into a first-time observed cofactor pocket located at the concaved interface of 14-3-3β helices α2, α3, α4 through mainly electrostatic and hydrogen interactions. Such a Tricarboxylic Acid Cycle intermediate Malate bond model might offer a new approach to further analyze insulin-independent 14-3-3/ChREBP pathway of de novo fat synthesis in the liver.

Crystal Structure, 14-3-3 Protein, ChREBP, Transcription Activation, Malate, Malic Acid

Hou, Z. , Su, L. and Liu, X. (2017) Structural Basis for the Interaction of 14-3-3β with Tricarboxylic Acid Cycle Intermediate Malate. Journal of Biosciences and Medicines, 5, 36-47. doi: 10.4236/jbm.2017.58003.