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Determinants That Control the Specific Interactions between TAB1 and p38

The Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China,¹ Department of Immunology, The Scripps Research Institute, La Jolla, California 92037,² Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037,³ Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-8816⁴

Received 12 September 2005/ Returned for modification 11 October 2005/ Accepted 21 February 2006

Previous studies have revealed that transforming growth factor-ß-activated protein kinase 1 (TAB1) interacts with p38 and induces p38 autophosphorylation. Here, we examine the sequence requirements in TAB1 and p38 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 p38. Furthermore, a cryptic D-domain-like docking site was identified adjacent to the N terminus of Pro412, putting Pro412 in the _B+3 position of the docking site. Through mutational analysis, we found that the previously identified hydrophobic docking groove in p38 is involved in this interaction, whereas the CD domain and ED domain are not. Furthermore, chimeric analysis with p38ß (which does not bind to TAB1) revealed a previously unidentified locus of p38 comprising Thr218 and Ile275 that is essential for specific binding of p38 to TAB1. Converting either of these residues to the corresponding amino acid of p38ß abolishes p38 interaction with TAB1. These p38 mutants still can be fully activated by p38 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 p38 substrates and activators. This suggests that TAB1-induced autophosphorylation of p38 results from conformational changes that are similar but unique to those seen in p38 interactions with its substrates and activating kinases.

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