Structure and Biochemical Properties of PRL-1, a Phosphatase Implicated in Cell Growth, Differentiation, and Tumor Invasion

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• 作者：Jin-Peng Sun ; Wei-Qing Wang ; Heyi Yang ; Sijiu Liu ; Fubo Liang ; Alexander A. Fedorov ; Steven C. Almo ; and Zhong-Yin Zhang
• 刊名：Biochemistry
• 出版年：2005
• 出版时间：September 13, 2005
• 年：2005
• 卷：44
• 期：36
• 页码：12009 - 12021
• 全文大小：914K
• 年卷期：v.44,no.36(September 13, 2005)
• ISSN：1520-4995

文摘

The PRL (phosphatase of regenerating liver) phosphatases constitute a novel class of small,prenylated phosphatases that are implicated in promoting cell growth, differentiation, and tumor invasion,and represent attractive targets for anticancer therapy. Here we describe the crystal structures of nativePRL-1 as well as the catalytically inactive mutant PRL-1/C104S in complex with sulfate. PRL-1 existsas a trimer in the crystalline state, burying 1140 Ų of accessible surface area at each dimer interface.Trimerization creates a large, bipartite membrane-binding surface in which the exposed C-terminal basicresidues could cooperate with the adjacent prenylation group to anchor PRL-1 on the acidic inner membrane.Structural and kinetic analyses place PRL-1 in the family of dual specificity phopsphatases with closeststructural similarity to the Cdc14 phosphatase and provide a molecular basis for catalytic activation ofthe PRL phosphatases. Finally, native PRL-1 is crystallized in an oxidized form in which a disulfide isformed between the active site Cys104 and a neighboring residue Cys49, which blocks both substratebinding and catalysis. Biochemical studies in solution and in the cell support a potential regulatory roleof this intramolecular disulfide bond formation in response to reactive oxygen species such as H₂O₂.