Jennifer
Laurence
Assistant Professor
Pharmaceutical Chemistry
Post-translational Regulation of the Tyrosine Phosphatase PRL-1
Mentor:
Christian
Schoneich
The long-term objective of the proposed research is to characterize how inherent conformational dynamics of the protein tyrosine phosphatase (PTPase) PRL-1 are stabilized by modification and how modification influences phosphatase activity and cellular function. PRLs were originally identified as early response genes that promote liver regeneration in rats after partial hepatectomy. More recently, over-expression of these enzymes was found to trigger metastasis and promote tumor formation. In each case phosphatase activity is required, but the protein is localized to a unique cellular location. This makes it critical to identify biochemical switches that direct differential cellular localization and outcomes.
Signaling is accomplished through transient, specific interactions driven by changes in structure, which are often influenced by chemical modification. These modifications act as switches in molecular function, controlling important biological processes. The specific role of PRL-1 in regulating signals related to cell growth has not been determined, nor is it known how PRL-1 itself is regulated.
Standard heteronuclear solution NMR methods will be used to assign chemical shift resonances and obtain restraints for structure calculations. Relaxation analysis will be used to characterize the dynamic motion of backbone amides in the protein and provide information about conformational changes involved in interconversion between the open and closed states, which are regulated by the redox state of the active site Cys. The affect of Tyr phosphorylation on PRL-1 activity is regulated by disulfide formation and post-translational modification will provide critical details to identify which conformation of PRL-1 to target for drug design.
Copyright © 2008
Center for Biomedical Research Excellence in Protein Structure and Function
Department of Medicinal Chemistry, School of Pharmacy
The University of KansasContact webmaster with comments about this web site.
