Trends in Cell Biology
OpinionPinning down proline-directed phosphorylation signaling
Section snippets
A unique conformational switch in the pSer/Thr-Pro bonds
Proline residues exist in two completely distinct cis and trans conformations and can provide a ‘backbone switch’ in proteins controlled by peptidyl-prolyl isomerization (Box 1). This intrinsically rather slow conversion is catalyzed by PPIases, which play an important role in protein folding or refolding 10, 14. There are two well-known families of PPIases – cyclophilins and FK506 binding proteins (FKBPs). However, they can be deleted entirely in yeast, and the biological importance of their
Catalysis of the conformational switch by Pin1 and Pin1-type PPIases
Pin1-type PPIases are enzymes that specifically isomerize pSer/Thr-Pro bonds [12]. Pin1 homologs are highly conserved in eukaryotes 9, 22, 23, 24. Interestingly, the budding yeast homolog was isolated a long time ago but was of unknown activity 25, 26. With the exception of plant enzymes, most other Pin1-type PPIases also contain a WW domain, a protein-interacting module present in many different proteins [8] (Fig. 1a). Various studies indicate that the WW domain targets the enzyme to its
Pin1 biological functions
Human Pin1 was originally identified by its ability to interact with the Aspergillus mitotic kinase NIMA and suppress the ability of NIMA to induce mitotic catastrophe [11]. This physical and functional interaction has been confirmed in Aspergillus ([36]; A.R. Means, pers. commun.). Various studies have supported a role for Pin1 in mitotic regulation and also suggested important roles for Pin1 in many other cellular processes under normal and pathological conditions.
Subcellular localization
Although Pin1 localizes primarily in the nucleus in cultured cells [11], it is readily detected in both the nucleus and cytoplasm in many dividing cells in normal and cancerous human tissues 32, 33, 34. In AD neurons, Pin1 is redistributed to cytoplasmic tangles [31]. Given that Pin1 is a small 18-kDa protein and does not have a defined nuclear localization signal [13], the distribution of Pin1 in the cell might be driven by its target proteins. Indeed, the interaction between the WW domain and
Alzheimer's disease
Many proteins, including tau, are hyperphosphorylated on Ser/Thr-Pro motifs in the brains of AD patients [5]. There is increasing evidence that inappropriate activation of mitotic events might contribute to hyperphosphorylation and disease development [5]. However, it remains to be determined how mitotic events occur in the neuron and how they lead to neurodegeneration. Interestingly, Pin1 is depleted in AD brain owing to its tight interactions with the tangles [31]. Importantly, Pin1 can
Phosphorylation-specific prolyl isomerization as a timing mechanism
Why would the cell employ phosphorylation-specific prolyl isomerization as an additional regulatory mechanism after proteins have been phosphorylated? The answer might lie in the unique structure and the crucial regulatory role of the pSer/Thr-Pro motifs. Based on analysis of ∼1% of total Ser/Thr-Pro bonds available in the protein structure database, the propensity of cis bond formation is in the range of 7–25% [27]. Because phosphorylation on Ser/Thr-Pro motifs in peptides does not greatly
Concluding remarks
Recent studies indicate that phosphorylation-dependent prolyl isomerization is a post-phosphorylation signaling mechanism that might play an important role in diverse cellular processes such as the cell cycle and transcription. Furthermore, this mechanism might provide novel insights into the pathogenesis of some human diseases such as AD and cancer. A major challenge for the future will be to determine how Pin1 actually induces conformational changes in phosphoproteins at the molecular level,
Acknowledgements
We are grateful to Tony Means and Tony Hunter for sharing results before publication, to Tony Hunter, Tony Means and Lew Cantley for critically reading the manuscript, and to the members of the Lu laboratory for stimulating discussions. We are sorry for not including all relevant references owing to space constraints. Y.C.L. is a fellow of the National Sciences and Engineering Research Council of Canada, and K.P.L. is a Pew Scholar and a Leukemia and Lymphoma Society Scholar. Our research cited
References (61)
- et al.
New wrinkles for an old domain
Cell
(2000) Prolyl isomerase and nuclear function
Cell
(1998)Structural and functional analysis of the mitotic peptidyl-prolyl isomerase Pin1 suggests that substrate recognition is phosphorylation dependent
Cell
(1997)A novel peptidyl-prolyl cis/trans isomerase from Escherichia coli
FEBS Lett.
(1994)Identification and characterization of a 14 kDa human protein as a novel parvulin-like peptidyl prolyl cis/trans isomerase
FEBS Lett.
(1999)Evidence that the substrate backbone conformation is critical to phosphorylation by p42 MAP kinase
FEBS Lett.
(2000)p13(SUC1) and the WW domain of PIN1 bind to the same phosphothreonine-proline epitope
J. Biol. Chem.
(2001)Functional conservation of phosphorylation-specific prolyl isomerases in plants
J. Biol. Chem.
(2001)Functional replacement of the essential ESS1 in yeast by the plant parvulin DlPar13
J. Biol. Chem.
(2001)PTF1 encodes an essential protein in Saccharomyces cerevisiae, which shows strong homology with a new putative family of PPIases
FEBS Lett.
(1995)
Pin1-dependent prolyl isomerization regulates dephosphorylation of Cdc25C and tau proteins
Mol. Cell
1H NMR study on the binding of Pin1 Trp-Trp domain with phosphothreonine peptides
J. Biol. Chem.
Mutations in a peptidylprolyl-cis/trans-isomerase gene lead to a defect in 3′-end formation of a pre-mRNA in Saccharomyces cerevisiae
J. Biol. Chem.
Role of WW domain phosphorylation in regulating its phosphoserine-binding activity and the Pin1 function
J. Biol. Chem.
Pin1 acts catalytically to promote a conformational change in Cdc25
Mol. Cell
The Xenopus Suc1/Cks protein promotes the phosphorylation of G(2)/M regulators
J. Biol. Chem.
Microtubule-targeting drugs induce Bcl-2 phosphorylation and association with Pin1
Neoplasia
Phosphorylation and cell cycle-dependent regulation of the Na+/H+ exchanger regulatory factor (NHERF-1) by cdc2 kinase
J. Biol. Chem.
Identification of a novel kinesin-related protein KRMP1 as a target for mitotic peptidyl-prolyl isomerase Pin1
J. Biol. Chem.
Crosstalk of prolyl isomerases, Pin1/Ess1, and cyclophilin A
Nucleic Biochem. Biophys. Res. Commun.
Mice lacking Pin1 develop normally, but are defective in entering cell cycle from G(0) arrest
Biochem. Biophys. Res. Commun.
Cyclin D1 provides a link between development and oncogenesis in the retina and breast
Cell
Specific interaction between the telomeric protein Pin2/TRF1 and the mitotic spindle
Curr. Biol.
Mitotic kinases as regulators of cell division and its checkpoints
Nat. Rev. Mol. Cell Biol.
Transcription factor AP-1 regulation by mitogen-activated protein kinase signal transduction pathways
J. Mol. Med.
Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions
Endocr. Rev.
Protein dephosphorylation and the intracellular control of the cell number
Front. Biosci.
Signaling through scaffold, anchoring, and adaptor proteins
Science
Grabbing phosphoproteins
Nature
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