TITLE:
Structural Basis for the Interaction of 14-3-3β with Tricarboxylic Acid Cycle Intermediate Malate
AUTHORS:
Zhiqiang Hou, Lijing Su, Xiaoyan Liu
KEYWORDS:
Crystal Structure, 14-3-3 Protein, ChREBP, Transcription Activation, Malate, Malic Acid
JOURNAL NAME:
Journal of Biosciences and Medicines,
Vol.5 No.8,
August
3,
2017
ABSTRACT: 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.