Trimeric structure of PRL-1 phosphatase reveals an active enzyme conformation and regulation mechanisms.
The PRL phosphatases, which constitute a subfamily of the protein tyrosine phosphatases (PTPs), are implicated in oncogenic and metastatic processes. Here, we report the crystal structure of human PRL-1 determined at 2.7A resolution. The crystal structure reveals the shallow active-site pocket with highly hydrophobic character. A structural comparison with the previously determined NMR structure of PRL-3 exhibits significant differences in the active-site region. In the PRL-1 structure, a sulfate ion is bound to the active-site, providing stabilizing interactions to maintain the canonically found active conformation of PTPs, whereas the NMR structure exhibits an open conformation of the active-site. We also found that PRL-1 forms a trimer in the crystal and the trimer exists in the membrane fraction of cells, suggesting the possible biological regulation of PRL-1 activity by oligomerization. The detailed structural information on the active enzyme conformation and regulation of PRL-1 provides the structural basis for the development of potential inhibitors of PRL enzymes.
Jeong
Dae Gwin
DG
Center for Cellular Switch Protein Structure, Korea Research Institute of Bioscience and Biotechnology, 52 Euh-eun-dong, Yuseong-gu, Daejeon 305-806, South Korea.
Kim
Seung Jun
SJ
Kim
Jae Hoon
JH
Son
Jeong Hee
JH
Park
Mi Rim
MR
Lim
Sang Myoun
SM
Yoon
Tae-Sung
TS
Ryu
Seong Eon
SE
D000595:Amino Acid Sequence; D001665:Binding Sites; D018797:Cell Cycle Proteins; D018360:Crystallography, X-Ray; D019281:Dimerization; D004583:Electrons; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D017874:Immediate-Early Proteins / Q000737:chemistry*; D008027:Light; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008565:Membrane Proteins; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins; D010455:Peptides / Q000737:chemistry; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry*; D012542:Scattering, Radiation; D017386:Sequence Homology, Amino Acid; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013347:Subcellular Fractions; D013379:Substrate Specificity
D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D010455:Peptides; C490198:PTP4A1 protein, human; C484730:PTP4A3 protein, human; D017027:Protein Tyrosine Phosphatases