Crystal structure of the catalytic domain of human MAP kinase phosphatase 5: structural insight into constitutively active phosphatase.
MAP kinase phosphatase 5 (MKP5) is a member of the mitogen-activated protein kinase phosphatase (MKP) family and selectively dephosphorylates JNK and p38. We have determined the crystal structure of the catalytic domain of human MKP5 (MKP5-C) to 1.6 A. In previously reported MKP-C structures, the residues that constitute the active site are seriously deviated from the active conformation of protein tyrosine phosphatases (PTPs), which are accompanied by low catalytic activity. High activities of MKPs are achieved by binding their cognate substrates, representing substrate-induced activation. However, the MKP5-C structure adopts an active conformation of PTP even in the absence of its substrate binding, which is consistent with the previous results that MKP5 solely possesses the intrinsic activity. Further, we identify a sequence motif common to the members of MKPs having low catalytic activity by comparing structures and sequences of other MKPs. Our structural information provides an explanation of constitutive activity of MKP5 as well as the structural insight into substrate-induced activation occurred in other MKPs.
Jeong
Dae Gwin
DG
Systemic Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology, 52 Eoeun-Dong, Yuseong-Gu, Daejeon, 305-333, Republic of Korea.
Yoon
Tae-Sung
TS
Kim
Jae Hoon
JH
Shim
Mi Young
MY
Jung
Suk-Kyeong
SK
Son
Jeong Hee
JH
Ryu
Seong Eon
SE
Kim
Seung Jun
SJ
D000595:Amino Acid Sequence; D002384:Catalysis; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D054637:Dual-Specificity Phosphatases; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D054639:Mitogen-Activated Protein Kinase Phosphatases; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity
D047908:Intracellular Signaling Peptides and Proteins; C120407:DUSP10 protein, human; D054639:Mitogen-Activated Protein Kinase Phosphatases; D054637:Dual-Specificity Phosphatases; D017027:Protein Tyrosine Phosphatases