Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Biochemistry
2011 Aug 02;5030:6567-78. doi: 10.1021/bi200553e.
Show Gene links
Show Anatomy links
Molecular basis for an ancient partnership between prolyl isomerase Pin1 and phosphatase inhibitor-2.
Sami F
,
Smet-Nocca C
,
Khan M
,
Landrieu I
,
Lippens G
,
Brautigan DL
.
???displayArticle.abstract??? Pin1 is a prolyl isomerase that recognizes phosphorylated Ser/Thr-Pro sites, and phosphatase inhibitor-2 (I-2) is phosphorylated during mitosis at a PSpTP site that is expected to be a Pin1 substrate. However, we previously discovered I-2, but not phospho-I-2, bound to Pin1 as an allosteric modifier of Pin1 substrate specificity [Li, M., et al. (2008) Biochemistry 47, 292]. Here, we use binding assays and NMR spectroscopy to map the interactions on Pin1 and I-2 to elucidate the organization of this complex. Despite having sequences that are ∼50% identical, human, Xenopus, and Drosophila I-2 proteins all exhibited identical, saturable binding to GST-Pin1 with K(0.5) values of 0.3 μM. The (1)H-(15)N heteronuclear single-quantum coherence spectra for both the WW domain and isomerase domain of Pin1 showed distinctive shifts upon addition of I-2. Conversely, as shown by NMR spectroscopy, specific regions of I-2 were affected by addition of Pin1. A single-residue I68A substitution in I-2 weakened binding to Pin1 by half and essentially eliminated binding to the isolated WW domain. On the other hand, truncation of I-2 to residue 152 had a minimal effect on binding to the WW domain but eliminated binding to the isomerase domain. Size exclusion chromatography revealed that wild-type I-2 and Pin1 formed a large (>300 kDa) complex and I-2(I68A) formed a complex of half the size that we propose are a heterotetramer and a heterodimer, respectively. Pin1 and I-2 are conserved among eukaryotes from yeast to humans, and we propose they make up an ancient partnership that provides a means for regulating Pin1 specificity and function.
Ayala,
The prolyl isomerase Pin1 is a novel prognostic marker in human prostate cancer.
2003, Pubmed
Ayala,
The prolyl isomerase Pin1 is a novel prognostic marker in human prostate cancer.
2003,
Pubmed
Bao,
Prevalent overexpression of prolyl isomerase Pin1 in human cancers.
2004,
Pubmed
Bayer,
Structural analysis of the mitotic regulator hPin1 in solution: insights into domain architecture and substrate binding.
2003,
Pubmed
Dancheck,
Detailed structural characterization of unbound protein phosphatase 1 inhibitors.
2008,
Pubmed
Dancheck,
Molecular investigations of the structure and function of the protein phosphatase 1-spinophilin-inhibitor 2 heterotrimeric complex.
2011,
Pubmed
Eto,
Inhibitor-2 regulates protein phosphatase-1 complexed with NimA-related kinase to induce centrosome separation.
2002,
Pubmed
Hall,
Tensin1 requires protein phosphatase-1alpha in addition to RhoGAP DLC-1 to control cell polarization, migration, and invasion.
2009,
Pubmed
Hamdane,
Pin1 allows for differential Tau dephosphorylation in neuronal cells.
2006,
Pubmed
Hanes,
Sequence and mutational analysis of ESS1, a gene essential for growth in Saccharomyces cerevisiae.
1989,
Pubmed
Hemmings,
Reconstitution of a Mg-ATP-dependent protein phosphatase and its activation through a phosphorylation mechanism.
1982,
Pubmed
Hennig,
Selective inactivation of parvulin-like peptidyl-prolyl cis/trans isomerases by juglone.
1998,
Pubmed
Huang,
Separation and characterization of two phosphorylase phosphatase inhibitors from rabbit skeletal muscle.
1976,
Pubmed
Huang,
Characterization of the inhibition of protein phosphatase-1 by DARPP-32 and inhibitor-2.
1999,
Pubmed
Hurley,
Structural basis for regulation of protein phosphatase 1 by inhibitor-2.
2007,
Pubmed
Ingebritsen,
The protein phosphatases involved in cellular regulation. 1. Classification and substrate specificities.
1983,
Pubmed
Kim,
Pin1 overexpression in colorectal cancer and its correlation with aberrant beta-catenin expression.
2005,
Pubmed
Leach,
Phosphorylation of phosphatase inhibitor-2 at centrosomes during mitosis.
2003,
Pubmed
Li,
Phosphorylation of the Pro-X-Thr-Pro site in phosphatase inhibitor-2 by cyclin-dependent protein kinase during M-phase of the cell cycle.
2006,
Pubmed
Li,
Pin1 contributes to cervical tumorigenesis by regulating cyclin D1 expression.
2006,
Pubmed
Li,
Phosphorylation and functions of inhibitor-2 family of proteins.
2007,
Pubmed
,
Xenbase
Li,
Binding of phosphatase inhibitor-2 to prolyl isomerase Pin1 modifies specificity for mitotic phosphoproteins.
2008,
Pubmed
Lim,
Pinning down phosphorylated tau and tauopathies.
2005,
Pubmed
Lippens,
Molecular mechanisms of the phospho-dependent prolyl cis/trans isomerase Pin1.
2007,
Pubmed
Liu,
Mutations of the serine phosphorylated in the protein phosphatase-1-binding motif in the skeletal muscle glycogen-targeting subunit.
2000,
Pubmed
Lu,
Prolyl isomerase Pin1 as a molecular target for cancer diagnostics and therapeutics.
2003,
Pubmed
Lu,
A human peptidyl-prolyl isomerase essential for regulation of mitosis.
1996,
Pubmed
Lu,
Critical role of WW domain phosphorylation in regulating phosphoserine binding activity and Pin1 function.
2002,
Pubmed
Maleszka,
The dodo gene family encodes a novel protein involved in signal transduction and protein folding.
1997,
Pubmed
Puntoni,
Phosphorylation of the inhibitor-2 of protein phosphatase-1 by cdc2-cyclin B and GSK3.
1995,
Pubmed
Ranganathan,
Structural and functional analysis of the mitotic rotamase Pin1 suggests substrate recognition is phosphorylation dependent.
1997,
Pubmed
Ryo,
Prolyl isomerase Pin1: a catalyst for oncogenesis and a potential therapeutic target in cancer.
2003,
Pubmed
Satinover,
Activation of Aurora-A kinase by protein phosphatase inhibitor-2, a bifunctional signaling protein.
2004,
Pubmed
,
Xenbase
Satinover,
Aurora-A kinase and inhibitor-2 regulate the cyclin threshold for mitotic entry in Xenopus early embryonic cell cycles.
2006,
Pubmed
,
Xenbase
Schutkowski,
Role of phosphorylation in determining the backbone dynamics of the serine/threonine-proline motif and Pin1 substrate recognition.
1998,
Pubmed
Shen,
The essential mitotic peptidyl-prolyl isomerase Pin1 binds and regulates mitosis-specific phosphoproteins.
1998,
Pubmed
,
Xenbase
Terry-Lorenzo,
Neurabins recruit protein phosphatase-1 and inhibitor-2 to the actin cytoskeleton.
2002,
Pubmed
Wang,
A novel transmembrane Ser/Thr kinase complexes with protein phosphatase-1 and inhibitor-2.
2002,
Pubmed
Wang,
Phosphorylation and activation of the ATP-Mg-dependent protein phosphatase by the mitogen-activated protein kinase.
1995,
Pubmed
Wang,
Maternal phosphatase inhibitor-2 is required for proper chromosome segregation and mitotic synchrony during Drosophila embryogenesis.
2008,
Pubmed
Wang,
Phosphatase inhibitor-2 balances protein phosphatase 1 and aurora B kinase for chromosome segregation and cytokinesis in human retinal epithelial cells.
2008,
Pubmed
Wang,
Phosphatase inhibitor 2 promotes acetylation of tubulin in the primary cilium of human retinal epithelial cells.
2008,
Pubmed
Wildemann,
Nanomolar inhibitors of the peptidyl prolyl cis/trans isomerase Pin1 from combinatorial peptide libraries.
2006,
Pubmed
Winkler,
Requirement of the prolyl isomerase Pin1 for the replication checkpoint.
2000,
Pubmed
,
Xenbase
Wulf,
Pin1 is overexpressed in breast cancer and cooperates with Ras signaling in increasing the transcriptional activity of c-Jun towards cyclin D1.
2001,
Pubmed
Wulf,
Role of Pin1 in the regulation of p53 stability and p21 transactivation, and cell cycle checkpoints in response to DNA damage.
2002,
Pubmed
Wulf,
The prolyl isomerase Pin1 in breast development and cancer.
2003,
Pubmed
Xu,
Pin1 as an anticancer drug target.
2009,
Pubmed
Yaffe,
Sequence-specific and phosphorylation-dependent proline isomerization: a potential mitotic regulatory mechanism.
1997,
Pubmed
Yeh,
A signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cells.
2004,
Pubmed
Zhao,
A phosphorylated prodrug for the inhibition of Pin1.
2007,
Pubmed
Zheng,
The prolyl isomerase Pin1 is a regulator of p53 in genotoxic response.
2002,
Pubmed
Zhou,
Aberrant expression of beta-catenin, Pin1 and cylin D1 in salivary adenoid cystic carcinoma: relation to tumor proliferation and metastasis.
2006,
Pubmed
Zhou,
Pin1-dependent prolyl isomerization regulates dephosphorylation of Cdc25C and tau proteins.
2000,
Pubmed