Crystal structures of MAP kinase p38 complexed to the docking sites on its nuclear substrate MEF2A and activator MKK3b.
The structures of the MAP kinase p38 in complex with docking site peptides containing a phi(A)-X-phi(B) motif, derived from substrate MEF2A and activating enzyme MKK3b, have been solved. The peptides bind to the same site in the C-terminal domain of the kinase, which is both outside the active site and distinct from the "CD" domain previously implicated in docking site interactions. Mutational analysis on the interaction of p38 with the docking sites supports the crystallographic models and has uncovered two novel residues on the docking groove that are critical for binding. The two peptides induce similar large conformational changes local to the peptide binding groove. The peptides also induce unexpected and different conformational changes in the active site, as well as structural disorder in the phosphorylation lip.
Chang
Chung I
CI
Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Xu
Bing-e
BE
Akella
Radha
R
Cobb
Melanie H
MH
Goldsmith
Elizabeth J
EJ
D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D026161:MADS Domain Proteins; D048371:MAP Kinase Kinase 3; D064326:MEF2 Transcription Factors; D020929:Mitogen-Activated Protein Kinase Kinases / Q000737:chemistry* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D016297:Mutagenesis, Site-Directed; D018006:Myogenic Regulatory Factors; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D020836:Protein Structure, Quaternary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry* / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D004268:DNA-Binding Proteins; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578035:MEF2A protein, human; D018006:Myogenic Regulatory Factors; D010455:Peptides; D014157:Transcription Factors; D000255:Adenosine Triphosphate; D011505:Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; C482530:MAP2K3 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases