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Review
. 2024 Apr 23;13(9):731.
doi: 10.3390/cells13090731.

Pin1-Catalyzed Conformation Changes Regulate Protein Ubiquitination and Degradation

Jessica Jeong  1   2 , Muhammad Usman  1   2 , Yitong Li  1   2 , Xiao Zhen Zhou  1   3   4 , Kun Ping Lu  1   2
Affiliations
Review

Pin1-Catalyzed Conformation Changes Regulate Protein Ubiquitination and Degradation

Jessica Jeong et al. Cells. .

Abstract

The unique prolyl isomerase Pin1 binds to and catalyzes cis-trans conformational changes of specific Ser/Thr-Pro motifs after phosphorylation, thereby playing a pivotal role in regulating the structure and function of its protein substrates. In particular, Pin1 activity regulates the affinity of a substrate for E3 ubiquitin ligases, thereby modulating the turnover of a subset of proteins and coordinating their activities after phosphorylation in both physiological and disease states. In this review, we highlight recent advancements in Pin1-regulated ubiquitination in the context of cancer and neurodegenerative disease. Specifically, Pin1 promotes cancer progression by increasing the stabilities of numerous oncoproteins and decreasing the stabilities of many tumor suppressors. Meanwhile, Pin1 plays a critical role in different neurodegenerative disorders via the regulation of protein turnover. Finally, we propose a novel therapeutic approach wherein the ubiquitin-proteasome system can be leveraged for therapy by targeting pathogenic intracellular targets for TRIM21-dependent degradation using stereospecific antibodies.

Keywords: E3 ligase; Pin1; TRIM21; cancer; cis–trans conformational changes; neurodegeneration; phosphorylation signaling; protein ubiquitination; proteosome pathway.

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Conflict of interest statement

X.Z.Z. and K.P.L. are the scientific founders and former scientific advisors of Pinteon, in which they own equity, as well as the inventors of several issued patents and/or pending patent applications related to Pin1. Their interests were reviewed and are managed by Western University in accordance with its conflict-of-interest policy. The remaining authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Overview of Pin1 involvement in ubiquitin-mediated degradation. After Pin1 binds and catalyzes a conformational change to a phosphorylated substrate, the resulting protein may have either decreased or increased susceptibility to ubiquitin-mediated degradation, depending on the molecular characteristics of the new conformation. Specifically, the resulting configuration may have an altered susceptibility to other post-translational mechanisms and polyubiquitination, as well as an affinity with ubiquitin factors. Furthermore, because Pin1 negatively regulates many E3 ligases, it may indirectly play a role in the stability of the substrate of these ubiquitin factors as well.
Figure 2
Figure 2
Stereospecific antibodies selectively deplete extracellular and intracellular cis P-tau. Pin1 plays a physiological role in safeguarding neurons against pathogenic cis-P-tau accumulation and neurofibrillary tangle formation by catalyzing the cis–trans isomerization of tau. However, when Pin1 is depleted during brain injury, cis-P-tau can accumulate and result in tau-associated neurodegeneration. Upon treatment with stereospecific cis-P-tau antibodies, cis-P-tau antibodies may bind to the p-Ser/Thr residues of their antigen and capture it extracellularly or intracellularly. Regardless, the antibody or antibody–antigen complexes enter the cell via Fc-receptor endocytosis. Finally, the TRIM21 E3 ligase engages the Fc region of the antibody, facilitating the ubiquitination and subsequent degradation of the TRIM21–antibody–antigen complex while sparing trans-P-tau or unphosphorylated, unaltered tau to carry out their physiological functions.
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