Study of cis/trans proline isomerization as a nove.. (ProProteinRegulation)
Study of cis/trans proline isomerization as a novel regulatory mechanism of protein function
Start date: Sep 1, 2012,
End date: Aug 31, 2016
Cellular processes are regulated through wide and complex signaling networks that require a tight spatial and temporal control over protein function. Recently a growing body of evidence has emerged supporting the role of prolyl cis-trans isomerization as a new intrinsic molecular regulatory mechanism with important consequences for protein function. Proline is the only amino acid in proteins that depending on the value of the ω angle of the peptidic bond can adopt two completely different conformations (cis or trans), which can have important consequences for protein structure. Furthermore, the slow inter-conversion between these two conformations provides a regulatory mechanism of protein structure and enzymes (named peptidyl prolyl isomerases, PPIases) able to catalyze the isomerization exist. The recent discovery of the phospho-specific PPIase Pin1 implied a new regulatory role for this family of enzymes. Pin1 has been shown to be involved in the control of cell-cycle, growth factors and apoptosis and its deregulation to be implicated in cancer, asthma and neurodegenerative diseases. However, the study of the exact effect of cis/trans proline isomerization in protein function and the role of PPIases (specifically Pin1) in biological networks has been deeply hampered by the intrinsic nature of this non-covalent modification which can be safely defined as the most subtle of the ones currently known. Here we propose to adopt a Chemical Biology approach in order to study some of the unanswered questions about Pin1 difficult to address through more traditional methods. We will try to elucidate Pin1’s mechanism of action, the different biological function between cis and trans conformations of its substrates and develop a new method to monitor its activity. We expect this project will make an important contribution towards the understanding of Pin1 in protein function regulation and the validation of its potential as a new therapeutic and diagnosis target for cancer.
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