A Single Amino Acid in the Hinge Loop Region of the FOXP Forkhead Domain is Significant for Dimerisation

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• 作者：Kershia Perumal ; Heini W. Dirr ; Sylvia Fanucchi
• 关键词：Forkhead ; Domain swapping ; Hinge region ; Transcription factor ; FOXP2 ; Hydrophobic interface
• 刊名：The Protein Journal
• 出版年：2015
• 出版时间：April 2015
• 年：2015
• 卷：34
• 期：2
• 页码：111-121
• 全文大小：1,326 KB
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• 作者单位：Kershia Perumal (1)
  Heini W. Dirr (1)
  Sylvia Fanucchi (1)
  
  1. Protein Structure-Function Research Unit, School of Molecular and Cell Biology, University of the Witwatersrand, 1 Jan Smuts Ave, Johannesburg, 2050, South Africa
  
• 刊物类别：Chemistry and Materials Science
• 刊物主题：Chemistry
  Bioorganic Chemistry
  Biochemistry
  Organic Chemistry
  Animal Anatomy, Morphology and Histology
  
• 出版者：Springer Netherlands
• ISSN：1573-4943

文摘

The forkhead box (FOX) proteins are a family of transcription factors that interact with DNA via a winged helix motif that forms part of the forkhead domain. The FOXP (FOXP1-) subfamily is unique in the family in that the forkhead domains of these proteins are able to dimerise via domain swapping. In this event, structural elements are exchanged via extension of the hinge loop region. Despite the high sequence homology among the FOXP subfamily members, the stability of their forkhead domain dimers varies, with FOXP3 forming the most stable dimer. An amino acid difference is observed in the hinge region of the FOXP subfamily where a tyrosine in all members is replaced with a phenylalanine in FOXP3. In this work, the role of phenylalanine at this position in the hinge region was investigated. This was done by creating the Y540F variant of the FOXP2 forkhead domain. The effect of the Y540F mutation on the structure, dimerisation propensity and DNA binding ability of the FOXP subfamily was investigated. The mutation altered the structure of the protein by decreasing the disorder of the backbone as measured by circular dichroism spectroscopy and by altering the local environment of the hinge region as measured by tryptophan fluorescence. The propensity of the forkhead domain to form a dimer was improved ~9.5 fold by the mutation. This was attributed to increased hydrophobicity at the dimer interface as well as altered tension in the hinge loop region. DNA binding assays indicated that the affinity for DNA was decreased by the mutation. Taken together, these findings suggest that domain swapping may modulate DNA binding.