title: Determinants of 14-3-3σ protein dimerization and function in drug and radiation resistance.
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 Leu(12) and Tyr(84) play important roles in 14-3-3σ dimerization, the non-core residue Phe(25) appears to be more important in controlling 14-3-3σ dimerization activity. Interestingly, a similar non-core residue (Val(81)) is less important than Phe(25) in contributing to 14-3-3σ dimerization. Furthermore, dissociating dimeric 14-3-3σ into monomers by mutating the Leu(12), Phe(25), 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.
authors.affiliation: From the Department of Pharmacology and Toxicology and.
authors.forename: Zhaomin
authors.initials: Z
authors.lastname: Li
authors.forename: Hui
authors.initials: H
authors.lastname: Peng
authors.forename: Li
authors.initials: L
authors.lastname: Qin
authors.forename: Jing
authors.initials: J
authors.lastname: Qi
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Zuo
authors.forename: Jing-Yuan
authors.initials: JY
authors.lastname: Liu
authors.forename: Jian-Ting
authors.initials: JT
authors.lastname: Zhang
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D002455:Cell Division / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D004249:DNA Damage; D004351:Drug Resistance / Q000502:physiology*; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D057809:HEK293 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D055503:Protein Multimerization / Q000502:physiology*; D020836:Protein Structure, Quaternary; D011836:Radiation Tolerance / Q000502:physiology*; D013329:Structure-Activity Relationship
chemical_list: D048948:14-3-3 Proteins; C572235:YWHAZ protein, human
keywords: 14-3-3σ; Cell Cycle; Cell Death; Dimerization; Drug Resistance; Protein Dynamics; Protein Folding; SAXS
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