Determinants that control the specific interactions between TAB1 and p38α

Huamin Zhou, Min Zheng, Jianming Chen, Changchuan Xie, Anand R. Kolatkar, Tyler Zarubin, Zhiyun Ye, Radha Akella, Shengcai Lin, Elizabeth J. Goldsmith, Jiahuai Han

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Abstract

Previous studies have revealed that transforming growth factor-β-activated protein kinase 1 (TAB1) interacts with p38α and induces p38α autophosphorylation. Here, we examine the sequence requirements in TAB1 and p38α that drive their interaction. Deletion and point mutations in TAB1 reveal that a proline residue in the C terminus of TAB1 (Pro412) is necessary for its interaction with p38α. Furthermore, a cryptic D-domain-like docking site was identified adjacent to the N terminus of Pro412, putting Pro412 in the φB+3 position of the docking site. Through mutational analysis, we found that the previously identified hydrophobic docking groove in p38α is involved in this interaction, whereas the CD domain and ED domain are not. Furthermore, chimeric analysis with p38β (which does not bind to TAB1) revealed a previously unidentified locus of p38α comprising Thr218 and Ile275 that is essential for specific binding of p38α to TAB1. Converting either of these residues to the corresponding amino acid of p38α abolishes p38α interaction with TAB1. These p38α mutants still can be fully activated by p38α upstream activating kinase mitogen-activated protein kinase kinase 6, but their basal activity and activation in response to some extracellular stimuli are reduced. Adjacent to Thr218 and Ile275 is a site where large conformational changes occur in the presence of docking-site peptides derived from p38α substrates and activators. This suggests that TAB1-induced autophosphorylation of p38α results from conformational changes that are similar but unique to those seen in p38α interactions with its substrates and activating kinases.

Original languageEnglish (US)
Pages (from-to)3824-3834
Number of pages11
JournalMolecular and cellular biology
Volume26
Issue number10
DOIs
StatePublished - May 1 2006

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Zhou, H., Zheng, M., Chen, J., Xie, C., Kolatkar, A. R., Zarubin, T., Ye, Z., Akella, R., Lin, S., Goldsmith, E. J., & Han, J. (2006). Determinants that control the specific interactions between TAB1 and p38α. Molecular and cellular biology, 26(10), 3824-3834. https://doi.org/10.1128/MCB.26.10.3824-3834.2006