Structural And Functional Study Of Atypical PDZ Protein TIP-1and Immunogenic Protein Of Streptococcus Suis Serotype2HP0197

PDZ domain is one of abundant and widely distributed known structuraldomains. PDZ domains usually have dynamic functions, and they generally act asscaffolds helping to assemble large molecular complexes. TIP-1is an unusual PDZprotein containing only a single PDZ domain， and lacking of otherprotein-interacting domains. It has been shown that TIP-1acts as an inhibitor ofWnt/β-catenin signaling pathway and causes the intracellular accumulation of Kir2.3.To uncover the molecular mechanism of how TIP-1binds to different ligands andregulates their function, we performed the structural studies of TIP-1with/withoutβ-catenin or with Kir2.3C-terminal peptide as well as biochemical and cellularexperiments. We found that the C-terminal peptide of β-catenin could form a β-sheetinteraction with the TIP-1protein; TIP-1binds β-catenin with high affinity bycooperative canonical binding pocket with a conserved hydrophobic pair of residues;there is a striking and significant conformational change in TIP-1as a consequenceof β-catenin peptide binding; the C-terminal peptide of kir2.3could also form aβ-sheet interaction with the TIP-1protein; the phosphorylation/dephosphorylation ofSer443within the C-terminal Kir2.3dynamically regulates the Kir2.3/TIP-1association; our results revealed the regulation mechanism of the kir2.3endocyticpathway.HP0197is a novelly identified immunogenic protein of Streptococcus suisserotype2, the structural study of its N-terminal18kD domain revealed the multiplehelix conformation of this domain, and the distribution of electric charges on itssurface attributes a lot to its binding with heparin. The C-terminal G5domainreveals a characteristic topology for the G5domain, suggesting that it may have celladhension-related functions.SAD kinases contribute a lot to neuronal polarization, and it is the regulator forboth neuronal polarity and synaptic organization in C. elegans. Through thestructural study of SAD-1catalytic domain, we found that this domain adopts a typical bilobed kinase fold. In the future, it would be interesting to investigatefunctional and regulatory mechanism of this kinase which requires more structuraland functional study.