Department of Biological Sciences* Department of Biochemistry
National University of Singapore
** Xiamen University, China ***
Pei Chee Song*, ** Xueji Wu*** Jobichen Chack* J. Sivaraman* ○Yih-Cherng Liou*
Peptidyl-prolyl isomerase Pin1 is an essential protein in regulating entry into mitosis by catalyzing the conformational change of a number of critical proteins. So far, more than 50 Pin1 targets have been identified, suggesting that Pin1 may play an important role in a diverse array of cellular processes including cell cycle control, transcription and splicing regulation, DNA replication checkpoint control, DNA damage response, neuronal survival, and germ cell development. Moreover, Pin1 function has been implicated in several human diseases. Notably, overexpression of Pin1 is prevalently found in many human cancers; whereas its inhibition induces apoptosis and contributes to neuronal death in Alzheimer’s disease. Structurally and functionally, Pin1 is a novel prolyl isomerase and specifically catalyzes cis/trans-isomerization of proline in the sequence of phosphorylated Ser/Thr-Pro. Although the first structure of Pin1 has been reported in 1997 along with the short peptide substrate complex (4 to 7 residues), very little are known about its catalytic mechanism and its interaction with the biological substrates. Therefore, in our current studies, we have focused on the structural and functional studies on Pin1 mutants. Several mutants’ crystal structures and in vitro peptide binding assay combined with functional studies in mammalian cells have been carried out. Together, these studies provide a deeper understanding of how Pin1 interacts with its biological target proteins and perhaps is eventually leading to effective drug design.