Molecular mechanisms of the phospho-dependent prolyl cis/trans isomerase Pin1.
Since its discovery 10 years ago, Pin1, a prolyl cis/trans isomerase essential for cell cycle progression, has been implicated in a large number of molecular processes related to human diseases, including cancer and Alzheimer's disease. Pin1 is made up of a WW interaction domain and a C-terminal catalytic subunit, and several high-resolution structures are available that have helped define its function. The enzymatic activity of Pin1 towards short peptides containing the pSer/Thr-Pro motif has been well documented, and we discuss the available evidence for the molecular mechanisms of its isomerase activity. We further focus on those studies that examine its cis/trans isomerase function using full-length protein substrates. The interpretation of this research has been further complicated by the observation that many of its pSer/Thr-Pro substrate motifs are located in natively unstructured regions of polypeptides, and are characterized by minor populations of the cis conformer. Finally, we review the data on the possibility of alternative modes of substrate binding and the complex role that Pin1 plays in the degradation of its substrates. After considering the available work, it seems that further analysis is required to determine whether binding or catalysis is the primary mechanism through which Pin1 affects cell cycle progression.
Lippens
G
G
CNRS UMR 8576 Unité de Glycobiologie Structurale et Fonctionnelle, Université des Sciences et Technologies de Lille 1-59655, Villeneuve d'Ascq, France. Guy.Lippens@univ-lille1.fr
Landrieu
I
I
Smet
C
C
D006801:Humans; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000737:chemistry / Q000502:physiology*; D010766:Phosphorylation
D000072340:NIMA-Interacting Peptidylprolyl Isomerase; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase