Determinants of 14-3-3σ protein dimerization and function in drug and radiation resistance

Zhaomin Li, Hui Peng, Li Qin, Jing Qi, Xiaobing Zuo, Jing Yuan Liu, Jian-Ting Zhang

Research output: Contribution to journalArticle

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Abstract

Many proteins exist and function as homodimers. Understanding the detailed mechanism driving the homodimerization is important and will impact future studies targeting the "undruggable" oncogenic protein dimers. In this study, we used 14-3-3σ as a model homodimeric protein and performed a systematic investigation of the potential roles of amino acid residues in the interface for homodimerization. Unlike other members of the conserved 14-3-3 protein family, 14-3-3σ prefers to form a homodimer with two subareas in the dimeric interface that has 180° symmetry. We found that both subareas of the dimeric interface are required to maintain full dimerization activity. Although the interfacial hydrophobic core residues Leu12 and Tyr 84 play important roles in 14-3-3σ dimerization, the non-core residue Phe25 appears to be more important in controlling 14-3-3σ dimerization activity. Interestingly, a similar non-core residue (Val81) is less important than Phe25 in contributing to 14-3-3σ dimerization. Furthermore, dissociating dimeric 14-3-3σ into monomers by mutating the Leu12, Phe25, or Tyr 84 dimerization residue individually diminished the function of 14-3-3σ in resisting drug-induced apoptosis and in arresting cells at G2/M phase in response to DNA-damaging treatment. Thus, dimerization appears to be required for the function of 14-3-3σ.

Original languageEnglish
Pages (from-to)31447-31457
Number of pages11
JournalJournal of Biological Chemistry
Volume288
Issue number44
DOIs
StatePublished - Nov 1 2013

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Protein Multimerization
14-3-3 Proteins
Dimerization
Drug Resistance
Radiation
Pharmaceutical Preparations
Proteins
G2 Phase
Cell Division
Dimers
Monomers
Apoptosis
Amino Acids
DNA

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Determinants of 14-3-3σ protein dimerization and function in drug and radiation resistance. / Li, Zhaomin; Peng, Hui; Qin, Li; Qi, Jing; Zuo, Xiaobing; Liu, Jing Yuan; Zhang, Jian-Ting.

In: Journal of Biological Chemistry, Vol. 288, No. 44, 01.11.2013, p. 31447-31457.

Research output: Contribution to journalArticle

Li, Zhaomin ; Peng, Hui ; Qin, Li ; Qi, Jing ; Zuo, Xiaobing ; Liu, Jing Yuan ; Zhang, Jian-Ting. / Determinants of 14-3-3σ protein dimerization and function in drug and radiation resistance. In: Journal of Biological Chemistry. 2013 ; Vol. 288, No. 44. pp. 31447-31457.
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