A tethering mechanism underlies Pin1-catalyzed proline cis-trans isomerization at a noncanonical site.

conformations on exchange regimes on the order of seconds to minutes. Pin1, a prolyl isomerase, catalyzes the isomerization of proline peptide bonds that contain a specific phospho-motif-a phosphorylated serine or threonine followed by a proline (pS/pT-P)-allowing for switch-like effects on target protein structure and function. One protein substrate of Pin1 is the nuclear receptor peroxisome proliferator activated receptor gamma (PPARγ), which is shown here to undergo Pin1-catalyzed isomerization at a noncanonical proline distal to a canonical pS/pT-P binding site. These studies lay the foundation for understanding the role of Pin1 in mediating PPARγ-regulated transcription and expand understanding of Pin1-catalyzed enzymatic activities and functions.