Dataset Information

A phosphorylated pseudokinase complex controls cell wall synthesis in mycobacteria.

ABSTRACT: Prokaryotic cell wall biosynthesis is coordinated with cell growth and division, but the mechanisms regulating this dynamic process remain obscure. Here, we describe a phosphorylation-dependent regulatory complex that controls peptidoglycan (PG) biosynthesis in Mycobacterium tuberculosis. We found that PknB, a PG-responsive Ser-Thr protein kinase (STPK), initiates complex assembly by phosphorylating a kinase-like domain in the essential PG biosynthetic protein, MviN. This domain was structurally diverged from active kinases and did not mediate phosphotransfer. Threonine phosphorylation of the pseudokinase domain recruited the FhaA protein through its forkhead-associated (FHA) domain. The crystal structure of this phosphorylated pseudokinase-FHA domain complex revealed the basis of FHA domain recognition, which included unexpected contacts distal to the phosphorylated threonine. Conditional degradation of these proteins in mycobacteria demonstrated that MviN was essential for growth and PG biosynthesis and that FhaA regulated these processes at the cell poles and septum. Controlling this spatially localized PG regulatory complex is only one of several cellular roles ascribed to PknB, suggesting that the capacity to coordinate signaling across multiple processes is an important feature conserved between eukaryotic and prokaryotic STPK networks.

SUBMITTER: Gee CL

PROVIDER: S-EPMC3664666 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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A phosphorylated pseudokinase complex controls cell wall synthesis in mycobacteria.

Gee Christine L CL Papavinasasundaram Kadamba G KG Blair Sloane R SR Baer Christina E CE Falick Arnold M AM King David S DS Griffin Jennifer E JE Venghatakrishnan Harene H Zukauskas Andrew A Wei Jun-Rong JR Dhiman Rakesh K RK Crick Dean C DC Rubin Eric J EJ Sassetti Christopher M CM Alber Tom T

Science signaling 20120124 208

Prokaryotic cell wall biosynthesis is coordinated with cell growth and division, but the mechanisms regulating this dynamic process remain obscure. Here, we describe a phosphorylation-dependent regulatory complex that controls peptidoglycan (PG) biosynthesis in Mycobacterium tuberculosis. We found that PknB, a PG-responsive Ser-Thr protein kinase (STPK), initiates complex assembly by phosphorylating a kinase-like domain in the essential PG biosynthetic protein, MviN. This domain was structurally ...[more]

PMID: 22275220

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Project description:Lipids are prominent components of the mycobacterial cell wall, and they play critical roles not only in maintaining biofilm formation but also in resisting environmental stress, including drug resistance. However, information regarding the mechanism mediating mycobacterial lipid synthesis remains limited. PatA is a membrane-associated acyltransferase and synthesizes phosphatidyl-myo-inositol mannosides (PIMs) in mycobacteria. Here, we found that PatA could regulate the synthesis of lipids (except mycolic acids) to maintain biofilm formation and environmental stress resistance in Mycolicibacterium smegmatis. Interestingly, the deletion of patA significantly enhanced isoniazid (INH) resistance in M. smegmatis, although it reduced bacterial biofilm formation. This might be due to the fact that the patA deletion promoted the synthesis of mycolic acids through an unknown synthesis pathway other than the reported fatty acid synthase (FAS) pathway, which could effectively counteract the inhibition by INH of mycolic acid synthesis in mycobacteria. Furthermore, the amino acid sequences and physiological functions of PatA were highly conserved in mycobacteria. Therefore, we found a mycolic acid synthesis pathway regulated by PatA in mycobacteria. In addition, PatA also affected biofilm formation and environmental stress resistance by regulating the synthesis of lipids (except mycolic acids) in mycobacteria. IMPORTANCE Tuberculosis, caused by Mycobacterium tuberculosis, leads to a large number of human deaths every year. This is so serious, which is due mainly to the drug resistance of mycobacteria. INH kills M. tuberculosis by inhibiting the synthesis of mycolic acids, which are synthesized by the FAS pathway. However, whether there is another mycolic acid synthesis pathway is unknown. In this study, we found a PatA-mediated mycolic acid synthesis pathway that led to INH resistance of in patA-deleted mutant. In addition, we first report the regulatory effect of PatA on mycobacterial biofilm formation, which could affect the bacterial response to environmental stress. Our findings represent a new model for regulating biofilm formation by mycobacteria. More importantly, the discovery of the PatA-mediated mycolic acid synthesis pathway indicates that the study of mycobacterial lipids has entered a new stage, and the enzymes might be new targets of antituberculosis drugs.

Dataset Information

A phosphorylated pseudokinase complex controls cell wall synthesis in mycobacteria.

Publications

A phosphorylated pseudokinase complex controls cell wall synthesis in mycobacteria.

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