Crystal structure of the MAP kinase binding domain and the catalytic domain of human MKP5.
MAP kinase phosphatases (MKPs) have crucial roles in regulating the signaling activity of MAP kinases and are potential targets for drug discovery against human diseases. These enzymes contain a catalytic domain (CD) as well as a binding domain (BD) that help recognize the target MAP kinase. We report here the crystal structures at up to 2.2 A resolution of the BD and CD of human MKP5 and compare them to the known structures from other MKPs. Dramatic structural differences are observed between the BD of MKP5 and that of MKP3 determined previously by NMR. In particular, the cluster of positively charged residues that is important for MAP kinase binding is located in completely different positions in the two structures, with a distance of 25 A between them. Moreover, this cluster is alpha-helical in MKP5, while it forms a loop followed by a beta-strand in MKP3. These large structural differences could be associated with the distinct substrate preferences of these phosphatases, but further studies are needed to confirm this. The CD of MKP5 is observed in an active conformation, and two loops in the active site have backbone shifts of up to 5 A relative to the inactive CDs from other MKPs.
Tao
Xiao
X
Department of Biological Sciences, Columbia University, New York, New York 10027, USA.
Tong
Liang
L
D000595:Amino Acid Sequence; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray / Q000379:methods*; D054637:Dual-Specificity Phosphatases; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry*; D054639:Mitogen-Activated Protein Kinase Phosphatases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D011485:Protein Binding; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry*; D016415:Sequence Alignment
D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases; C120407:DUSP10 protein, human; D054639:Mitogen-Activated Protein Kinase Phosphatases; D054637:Dual-Specificity Phosphatases; D017027:Protein Tyrosine Phosphatases