Determinants that control the specific interactions between TAB1 and p38α
Anand R. Kolatkar
Elizabeth J. Goldsmith
- 生命科学－已发表论文 
Previous studies have revealed that transforming growth factor-beta-activated protein kinase 1 (TAB1) interacts with p38 alpha and induces p38 alpha autophosphorylation. Here, we examine the sequence requirements in TAB1 and p38 alpha 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 alpha. Furthermore, a cryptic D-domain-like docking site was identified adjacent to the N terminus of Pro412, putting Pro412 in the (phi(B)+3 position of the docking site. Through mutational analysis, we found that the previously identified hydrophobic docking groove in p38 alpha is involved in this interaction, whereas the CD domain and ED domain are not. Furthermore, chimeric analysis with p38 beta (which does not bind to TAB1) revealed a previously unidentified locus of p38 alpha comprising Thr218 and Ile275 that is essential for specific binding of p38 alpha to TAB1. Converting either of these residues to the corresponding amino acid of p380 abolishes p38 alpha interaction with TAB1. These p38a mutants still can be fully activated by p38 alpha 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 alpha substrates and activators. This suggests that TAB1-induced autophosphorylation of p38 alpha results from conformational changes that are similar but unique to those seen in p38 alpha interactions with its substrates and activating kinases.
CitationMOLECULAR AND CELLULAR BIOLOGY,2006,26(10):3824-34