Trends in Cell Biology
Volume 12, Issue 4, 1 April 2002, Pages 164-172
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Pinning down proline-directed phosphorylation signaling

https://doi.org/10.1016/S0962-8924(02)02253-5Get rights and content

Abstract

The reversible phosphorylation of proteins on serine or threonine residues preceding proline (Ser/Thr-Pro) is a major cellular signaling mechanism. Although it is proposed that phosphorylation regulates the function of proteins by inducing a conformational change, there are few clues about the actual conformational changes and their importance. Recent identification of the novel prolyl isomerase Pin1 that specifically isomerizes only the phosphorylated Ser/Thr-Pro bonds in certain proteins led us to propose a new signaling mechanism, whereby prolyl isomerization catalytically induces conformational changes in proteins following phosphorylation to regulate protein function. Emerging data indicate that such conformational changes have profound effects on catalytic activity, dephosphorylation, protein–protein interactions, subcellular location and/or turnover. Furthermore, this post-phosphorylation mechanism might play an important role in cell growth control and diseases such as cancer and Alzheimer's.

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

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