Peptidyl-prolyl cis/trans isomerases and transcription: is there a twist in the tail?

Abstract

Eukaryotic transcription is regulated predominantly by the post-translational modification of the participating components. One such modification is the cis-trans isomerization of peptidyl-prolyl bonds, which results in a conformational change in the protein involved. Enzymes that carry out this reaction include the yeast peptidyl-prolyl cis/trans isomerase Ess1 and its human counterpart Pin1, both of which recognize phosphorylated target motifs exclusively. Consequently, they operate together with proline-directed serine-threonine kinases and phosphatases. High-profile client proteins involved in transcription include steroid hormone receptors, cell-cycle regulators and immune mediators. Other key targets are elements of the transcription machinery, including the multiply phosphorylated carboxy-terminal domain of RNA polymerase II. Changes in isomerase activity have been shown to alter the transactivation potential, protein stability or intracellular localization of these client proteins. The resulting disruption to developmental processes and cell proliferation has been linked, in some cases, to human cancers.

Figure 1

The peptidyl-prolyl isomerase Pin1/Ess1 acts in three ways in transcriptional activation. In the first scenario (blue), PPI activity protects client proteins such as β-catenin and p53 from proteasomal degradation, allowing them to participate in promoter binding and gene activation. In the second scenario (red), conformational change triggers ubiquitin-dependent degradation by the proteasome (grey box), which might (for example, in the case of retinoic-acid receptor α or steroid-receptor coactivator-3) or might not (for example, in the case of c-Myc or interferon-regulatory factor 3) be linked to transcriptional potency. The third scenario (turquoise) involves direct interaction of Pin1 with the carboxy-terminal domain of RNA polymerase II (RNAP II), which has been implicated in downregulation of the polymerase during mitosis, polymerase recycling and elongation. PPI, peptidyl-prolyl isomerase.

Peter E. Shaw