Bacterial Cell Division Regulation by Ser/Thr Kinases: A Structural Perspective

Abstract

Recent genetic, biochemical and structural studies have established that eukaryotic-like Ser/Thr protein-kinases are critical mediators of developmental changes and host pathogen interactions in bacteria. Although with lower abundance compared to their homologues from eukaryotes, Ser/Thr protein-kinases are widespread in gram-positive bacteria. These data underline a key role of reversible Ser/Thr phosphorylation in bacterial physiology and virulence. Numerous studies have revealed how phosphorylation/dephosphorylation of Ser/Thr protein-kinases governs cell division and cell wall biosynthesis and that Ser/Thr protein kinases are responsible for distinct phenotypes, dependent on different environmental signals. In this review we discuss the current understandings of Ser/Thr protein-kinases functional processes based on structural data.

Protein Kinase B (PknB) of Mycobacterium tuberculosis Is Essential for Growth of the Pathogen in Vitro as well as for Survival within the Host

“…mediate important roles in cell division, growth, and development (49). Interactions of the extracellular PASTA domains of PrkC (a PknB ortholog in Bacillus subtilis) with muropeptides have been shown to be essential for germination of spores (5).…”

Differential thermodynamic behaviours of the extra-cellular regions of two Ser/Thr PrkC kinases revealed by calorimetric studies

“…STPK kinases are now known to regulate various cellular functions, such as biofilm formation [1], cell wall biosynthesis [2,3], cell division [2], sporulation [1,4], and stress response [5]. STPKs are one-component signal transduction systems, which combine both sensing and regulating properties [6]. Excellent work has examined the physiological role of protein kinases in cell division and growth in human pathogens [7][8][9].…”

Structural and binding properties of the PASTA domain of PonA2, a key penicillin binding protein from Mycobacterium tuberculosis

“…PASTA domains were also previously proposed to act as sensors of muropeptides and mediate complex mechanisms like bacterial revival from dormancy . In this scenario, hydrolysis of the PGN hydrolases is the first step, that has the twofold effect to alter the mechanical properties of the cell wall and produce specific PGN fragments . To investigate whether a similar muropeptide‐sensing mechanism is mediated by PonA2‐PASTA, we analyzed its possible binding to l ‐Ala‐gamma‐ d ‐Glu‐mDAP (Tri‐DAP) and MurNAc‐ l ‐Ala‐gamma‐ d ‐Glu‐mDAP (M‐Tri‐DAP), two muropeptides typically used to mimic the PGN peptide stem.…”

“…Depending on the amino acid located at the third position of the peptide stem, PGN is classified as either Lys‐type or meso‐diaminopimelic acid (DAP)‐type. Mycobacterium tuberculosis (Mtb), the etiologic agent of Tuberculosis, possesses a DAP‐type PGN, whose modeling is a key process in important cellular events, including cell growth, cell division, and resuscitation from dormancy …”

“…Similarly, PonA2 homolog in M. smegmatis was found to be important for bacterial adaptation in response to starvation or anaerobiosis . To understand if the PASTA domain of PonA2 could play a role as a target for β‐lactam antibiotics and/or as a sensor of muropeptides in the bacterial milieu , as observed for the Ser/Thr kinases PrkC and PknB, we determined its Nuclear Magnetic Resonance (NMR) structure and explored its binding properties toward the β‐lactam antibiotics cefuroxime and cefotaxime, the muropeptides l ‐Ala‐gamma‐ d ‐Glu‐mDAP and MurNAc‐ l ‐Ala‐gamma‐ d ‐Glu‐mDAP, and polymeric PGN. Results confirm a high conservation of the PASTA domain fold but highlight different behaviors and roles of these domains, likely depending on their specific surface residues.…”