Our results indicate that E-cadherin can be mono- and polyubiquitinated, and it is possible that both combination of ubiquitination are responsible for targeting E-cadherin for proteasomal degradation. Our results support the hypothesis that competitive Catharanthine sulfate binding between p120-catenin and modifications of E-cadherin by Hakai or Src at the JMD regulate E-cadherin degradation. While it is possible that p120catenin binding to the JMD may Mepiroxol inhibit Src or Hakai binding and hence ubiquitination and degradation, our results show that ubiquitination on at least K5 inhibits p120-catenin binding, and results in proteasomal degradation of E-cadherin. In a broader context, ubiquitination of E-cadherin JMD may block or even displace p120-catenin, resulting in E-cadherin internalization from the plasma membrane and rapid proteasomal degradation. Recent developments in bioinformatics have provided new tools for understanding relationships between protein sequence, structure, and function. Analysis of amino acid coevolution using 
information theory is one approach that has proven useful for a deeper appreciation of sequence relationships within protein families, and as a basis for interpreting functional roles of the coevolving residues. Recent studies of coevolving residues have revealed roles in protein stability, enzyme catalysis, intermolecular interactions, and macromolecular recognition. Methods such as coevolutionary analysis are increasingly necessary for deriving insights from the rapidly expanding quantities of sequence information, which far exceeds capacity for experimental investigation. As the methodologies for calculating coevolution continue to improve, this approach holds promise for providing insights as far-reaching and important as those routinely obtained from sequence conservation. Herein we apply recent approaches in coevolution to study a diverse enzyme family known as phosphomannomutase/phosphoglucomutase. PMM/PGM proteins comprise a widespread enzyme family involved in prokaryotic carbohydrate biosynthesis. They represent one sub-group of the aD-phosphohexomutase enzyme superfamily, according to their similar preference for glucose and mannose-based phosphosugar substrates. The enzyme reaction entails an intramolecular phosphoryl transfer reaction, converting a 1-phosphosugar into the corresponding 6-phosphosugar. The reaction proceeds via a bisphosphorylated sugar intermediate, is highly reversible, and dependent on Mg2+. A well-studied PMM/PGM is the enzyme from the human pathogen Pseudomonas aeruginosa. In this organism, PMM/PGM participates in the biosynthesis of several bacterial exoproducts involved in virulence of infections, including lipopolysaccharide, rhamnolipid, and alginate. In other bacteria, PMM/PGM proteins have varied biosynthetic roles and are also associated with virulence and resistance to antibiotics. Thus these enzymes are of potential interest for the development of inhibitors with clinical utility against bacterial infections. Structural and mechanistic studies of P. aeruginosa PMM/PGM have revealed key features of enzyme mechanism, including two distinct but overlapping binding modes for its 1- and 6phosphosugar substrate and product. Crystal structures of P. aeruginosa PMM/PGM have also shown that binding of ligand in the active site is accompanied by an interdomain conformational change of,10 degrees, via a hinge at the juncture of domains 3 and 4 of the protein. This conformational change permits residues in all four domains of the enzyme to participate in ligand contacts, and positions the substrate appropriately for phosphoryl transfer.