A pseudokinase mediates cell wall integrity inMycobacterium tuberculosis

Abstract

Microsymposia C62to determine the optical constants in a depth dependent manner. By modeling the reflectivity spectra, in combination with angular resolved reflectivity, we show that it is possible to extract accurate optical constants in cases intractable with current techniques. Due to the large number of parameters inherent in such free-form modeling, we use the maximum entropy method to refine the underlying model in fitting the measured reflectivity data. There is an abundance of data on protein interactions and protein complexes, both from conventional small-scale experiments collected over the decades, including three-dimensional structures, and more recently by large-scale functional genomics experiments. We can draw on this information to ask whether (i) non-functional protein interactions constrain protein sequences and (ii) whether protein structures harbor information about conformational changes upon binding to each other. KeywordsIn order to answer the first question, we project evolutionary and systems information onto 397, 196, and 701 proteins of known structure from E. coli, S. cerevisiae and H. sapiens respectively. We find that the propensity of proteins to interact in a non-specific manner with other proteins is inversely correlated with their abundance in E. coli and S. cerevisiae. This tendency is most pronounced at surface residues, suggesting that high abundance proteins have evolved to have a less sticky surface. In E. coli and S. cerevisiae, we also find that the evolutionary conservation of an amino acid is positively correlated with the stickiness of the surface environment around it. Thus, residues in sticky surface patches are evolutionarily more constrained, possibly because they are more likely to trigger non-functional interactions if they mutate. Although significant, the impact of protein stickiness is comparatively small in shaping the physico-chemical properties and evolution of H. sapiens proteins. This suggests that promiscuous protein-protein interactions are freer to accumulate in species with a small effective population size; a phenomenon akin to junk DNA accumulation.While non-functional interactions shape protein sequence and structure, functional protein interactions require not just sequence but also structural complementarity, which often involves conformational changes. We have analyzed the relationships between the structures of proteins and the conformational changes that they undergo upon binding. We find that the relative solvent accessible surface area of both free and bound subunits can be used to predict the magnitude of binding-induced conformational changes. We demonstrate that the relative solvent accessible surface area of monomeric proteins is useful as a simple proxy for intrinsic flexibility and for predicting conformational changes upon binding. In addition to the predictive power of this correlation, it reveals a strong connection between the flexibility of unbound proteins and their binding-induced conformational changes, consistent with the conf...

New substrates and interactors of the mycobacterial Serine/Threonine protein kinase PknG identified by a tailored interactomic approach

“…FhaA is a two-domain protein with a C-terminal FHA domain and a N-terminal domain of unknown function connected via a long unstructured linker region (300 residues in M. tuberculosis)[50]. The fhaA gene is encoded by a highly conserved mycobacterial operon involved in the control of cell shape and cell division[64]. A previous study described the recruitment of FhaA by a phosphorylated Thr residue in the pseudokinase…”

“…MviN and the involvement of this complex in mycobacterial cell wall biosynthesis[64]. Global phosphoproteomic studies in mycobacteria showed that FhaA is phosphorylated in vivo both on Thr and on Tyr, however the kinase(s) responsible(s) for each phosphorylation event are still poorly characterized.[49].…”