Prolyl isomerases and nuclear function.

The c-Myb/Cyp40 interaction raises the question of whether other transcription factors are regulated by PPIases. The only other example of a transcription factor that may be regulated by PPIase action is the zinc finger protein YY1, which interacts with CypA and FKBP12 (Yang et al. 1995xYang, W.M, Inouye, C.J, and Seto, E. J. Biol. Chem. 1995; 270: 15187–15193CrossRef | PubMed | Scopus (81)See all ReferencesYang et al. 1995). What about the regulation of other nuclear functions by PPIases? FKBP25 is nuclear and interacts with casein kinase II and nucleolin (Jin and Burakoff 1993xJin, Y.J and Burakoff, S.J. Proc. Natl. Acad. Sci. USA. 1993; 90: 7769–7773CrossRef | PubMedSee all ReferencesJin and Burakoff 1993). The functional significance of these interactions is unclear, but Fpr3p, the yeast counterpart of FKBP25, is localized to the nucleolus, suggesting that it functions there.Exogenously expressed Pin1 is localized to the spliceosome speckle in the nucleus, but the whereabouts of endogenous Pin1 has not been ascertained. As discussed above, Pin1/Ess1p is unique in that its action on protein substrates is phosphorylation dependent. Many of the mitotic phosphoproteins that Pin1 binds to are cyclin/Cdk targets and the consensus Pin1-binding site can be phosphorylated by cyclin/Cdks. Pin1 may sequester and/or inactivate phosphoproteins, such as Cdc25, needed to trigger the G2/M transition, thus regulating the exact timing of G2/M (1xCrenshaw, D.G, Yang, J, Means, A.R, and Kornbluth, S. EMBO J., in press. 1998; See all References, 20xShen, M, Stukenberg, P.T, Kirschner, M, and Lu, K.P. Genes Dev., in press. 1998; See all References). Although isomerization of prolyl peptide bonds usually occurs freely, rotation about a phospho-Ser/Thr Pro bond may be unusually hindered, and then catalysis by Pin1 could trigger a local conformational switch. For instance, the conformation of the phospho-Ser/Thr Pro bond could enhance or diminish dephosphorylation by a phosphatase, thus regulating the extent of phosphorylation by Cdk's, or facilitate its interaction with other proteins. However, it should be borne in mind that it has not been unequivocally established that Pin1's cell cycle function requires it to act as a PPIase as opposed to simply binding to its phosphorylated targets. This is an important issue, because parvulin has much lower activity in protein folding assays than on peptide substrates (Scholz et al. 1997axScholz, C, Rahfeld, J, Fischer, G, and Schmid, F.X. J. Mol. Biol. 1997; 273: 752–762CrossRef | PubMed | Scopus (41)See all ReferencesScholz et al. 1997a). The currently ascribed function of Pin1 is at the G2/M transition, but in principle it could also recognize substrates for other proline-directed protein kinases, such as MAP kinases, and thus have cell cycle independent functions.The fact that none of the yeast cyclophilins or FKBPs are essential implies that these PPIases do not have a critical nuclear function. However, although budding yeast has no additional PPIases of these types, there could be other novel types of PPIase. Nuclear function is increasingly recognized to involve the assembly and disassembly of macromolecular complexes, and these would make attractive targets for PPIases that could regulate protein–protein interactions through conformational changes.