Pin1

PIN1, or peptidyl-prolyl cis-trans isomerase NIMA-interacting 1, is a highly conserved enzyme that catalyzes cis-trans isomerization of specific phosphorylated serine/threonine-proline motifs in substrate proteins. This isomerization can alter the conformation, stability, localization, and interactions of target proteins, thereby modulating multiple cellular processes.

PIN1 is a two-domain protein. Its N-terminal WW domain binds phospho-Ser/Thr-Pro motifs, while its C-terminal catalytic PPIase domain carries out the isomerization. By bringing substrate motifs into an appropriate orientation, PIN1 can switch proteins between activity states, influencing downstream signaling and functional outcomes.

A broad set of substrates has been described, including tau, p53, cyclin D1, and Cdc25C, among others. Through these and related interactions, PIN1 participates in cell cycle progression, mitosis, DNA damage response, and signaling pathways such as NF-κB, Wnt, and MAPK. The effects of PIN1 are context dependent, promoting or modulating signaling outcomes by changing substrate conformation and interactions.

PIN1 is implicated in human disease. It is overexpressed in several cancers and is studied as a potential therapeutic target because its activity can stabilize oncogenic proteins and enhance proliferative signaling. In the brain, reduced PIN1 activity has been associated with tau hyperphosphorylation and aggregation, linking PIN1 to neurodegenerative processes such as Alzheimer's disease. Regulation of PIN1 occurs at transcriptional and post-translational levels, including oxidation, phosphorylation, and proteasomal degradation, reflecting tight control by cellular context.

Research into PIN1 includes the development of inhibitors as potential treatments for cancer and neurodegenerative diseases. Juglone is a known, non-specific PIN1 inhibitor, with more selective compounds under investigation.