Phosphorylation-dependent prolyl isomerization: a novel signaling regulatory mechanism

Citation
Xz. Zhou et al., Phosphorylation-dependent prolyl isomerization: a novel signaling regulatory mechanism, CELL MOL L, 56(9-10), 1999, pp. 788-806
Citations number
130
Language
INGLESE
art.tipo
Review
Categorie Soggetti
Cell & Developmental Biology
Journal title
CELLULAR AND MOLECULAR LIFE SCIENCES
ISSN journal
1420-682X → ACNP
Volume
56
Issue
9-10
Year of publication
1999
Pages
788 - 806
Database
ISI
SICI code
1420-682X(19991130)56:9-10<788:PPIANS>2.0.ZU;2-W
Abstract
Protein phosphorylation on serine or threonine residues preceding proline ( Ser/Thr-Pro) plays an essential role for regulating various cellular proces ses, including cell cycle progression. Although phosphorylation has been pr oposed to regulate the function of a protein by inducing conformational cha nges, much less is known about what phosphate additions actually do and how the functions of phosphoproteins are coordinated. Proline is important for determining protein structure because it exists in cis or trans conformati on and can put kinks into a polypeptide chain. We have shown that phosphory lation on Ser/Thr-Pro motifs reduces the cis/trans isomerization rate of Se r/Thr-Pro bonds. At the same time, proteins containing phosphorylated Ser/T hr-Pro motifs are substrates for the prolyl isomerase Pin1. The WW domain o f Pin1 acts as a phosphoserine/threonine-binding module binding a defined s ubset of mitosis-specific phosphoproteins, such as Cdc25 and tau. These int eractions target the enzymatic activity of Pin1 close to its substrates. In contrast to other prolyl isomerases (peptidylprolyl isomerases, PPIases), Pin1 has an extremely high degree of substrate specificity, specifically is omerizing phosphorylated Ser/Thr-Pro bonds. Therefore, Pin1 binds and regul ates the function of a defined subset of phosphoproteins. Furthermore, inhi biting Pin1 function is lethal for dividing cells. Interestingly,Pin1, whic h can restore the biological function of phosphorylated tau, is sequestered in the neurofibrillary tangles in Alzheimer's brains. Thus, we have propos ed a novel signaling regulatory mechanism, where protein phosphorylation cr eates binding sites for Pin1, which can then latch on to and isomerize the phosphorylated Ser/Thr-Pro peptide bond. In turn, this may change the shape of the protein, regulating its activity, dephosphorylation, degradation or location in the cell. This new post-phosphorylation regulatory mechanism a ppears to play an important role in normal cell function, such as mitotic p rogression, and in the pathogenesis of some human pathologies, such as Alzh eimer's disease.