The competitive binding studies of CMP inhibitor and polysialic acid (polySia) to the polybasic polysialyltransferase domain (PSTD) in the polysialyltransferase

Title : The competitive binding studies of CMP inhibitor and polysialic acid (polySia) to the polybasic polysialyltransferase domain (PSTD) in the polysialyltransferase

Abstract:

Polysialic acid (polySia) is a novel glycan that posttranslationally modifies neural cell adhesion molecules (NCAMs) in mammalian cells. Up-regulation of polySia-NCAM expression is associated with tumor progression in many metastatic cancers. Both members of the ST8Sia family of α2,8-polysialyltransferase (polyST), ST8Sia II (STX) and ST8Sia IV (PST), utilize CMP-Neu5Ac as the activated sugar nucleotide donor to catalyze polysialylation of NCAM. The previous immunoblotting studies suggested that heparin and cyclic monophosphate (CMP) are possible polysialyltransferase inhibitors, which can modulate migration in ST8SiaII-expressing tumour cells. In this study, we further found that the interaction between polySia and the polybasic polysialyltransferase domain (PSTD) in the polyST was inhibited is due to the formations of the PSTD-heparin or PSTD-CMP complex by using the methods of the circular dichroism (CD) spectroscopy, the Isothermal titration calorimetry (ITC) and NMR spectroscopy. Our findings indicate the competitive bindings exist between heparin or CMP and the PSTD, and between polySia and the PSTD. Incorporating the previous NMR results and the molecular modeling analysis into the current data of CD spectra and ITC data, we propose that an α-helix within ST8 Sia IV is a major contributor in modulating bindings of polySia to the PSTD or CMP inhibitor to the PSTD. These biophysical studies provide the insight for drug design of the inhibitors of neural cell adhesion molecule (NCAM) polysialylation.

Audience take away:
Help the audience to use much simpler and less time consuming methods to identify potential inhibitors.

Biography:

Dr. Guo-Ping Zhou is currently a Distinguished Professor of Gordon Life Science Institute, USA. He is also an Adjunct Professor of several academics in the United States and China.  Dr. Zhou received his Ph.D in Bio-physics from University of California at Davis, and completed his postdoctoral training at Stanford Univer-sity and Harvard University, respectively.  Dr. Zhou determined the 3D NMR structures of some proteins, protein-DNA complexes, super lipids such as dolichol and other polyisoprenyls, as well as polyisoprenol recognition sequences. Dr. Zhou has successfully introduced the elegant wenxiang diagrams to elucidate the mechanisms of the coiled-coil proteins, protein-lipids, protein-DNA interactions, and prion protein mis-folding observed by NMR. Meanwhile, he has also published many papers in Bioinformatics. Dr. Zhou’s current research is focused on investigation into the relationship between the functions and structures of polysialyltransferases. In addition, as Editorial Board Member, Guest Editor and Bentham Brand Ambassa-dor, Zhou has edited some special issues on structural biology for several influential scientific journals.