Mycobacterium tuberculosis Serine/Threonine Protein Kinases

Abstract

The Mycobacterium tuberculosis genome encodes 11 serine/threonine protein kinases (STPKs). A similar number of two-component systems are also present, indicating that these two signal transduction mechanisms are both important in the adaptation of this bacterial pathogen to its environment. The M. tuberculosis phosphoproteome includes hundreds of Ser- and Thr-phosphorylated proteins that participate in all aspects of M. tuberculosis biology, supporting a critical role for the STPKs in regulating M. tuberculosis physiology. Nine of the STPKs are receptor type kinases, with an extracytoplasmic sensor domain and an intracellular kinase domain, indicating that these kinases transduce external signals. Two other STPKs are cytoplasmic and have regulatory domains that sense changes within the cell. Structural analysis of some of the STPKs has led to advances in our understanding of the mechanisms by which these STPKs are activated and regulated. Functional analysis has provided insights into the effects of phosphorylation on the activity of several proteins, but for most phosphoproteins the role of phosphorylation in regulating function is unknown. Major future challenges include characterizing the functional effects of phosphorylation for this large number of phosphoproteins, identifying the cognate STPKs for these phosphoproteins, and determining the signals that the STPKs sense. Ultimately, combining these STPK-regulated processes into larger, integrated regulatory networks will provide deeper insight into M. tuberculosis adaptive mechanisms that contribute to tuberculosis pathogenesis. Finally, the STPKs offer attractive targets for inhibitor development that may lead to new therapies for drug-susceptible and drug-resistant tuberculosis.

The crystal structure of the catalytic domain of the ser/thr kinase PknA from M. tuberculosis shows an Src-like autoinhibited conformation

“…Originally thought to be restricted to the eukaryotic kingdom, reversible protein phosphorylation on serine, threonine and tyrosine residues has emerged as a widespread signaling mechanism in prokaryotes and has turned into a highly active field of research in modern molecular microbiology. Mycobacterium tuberculosis was among the first microorganisms for which genomic data indicated the presence of eukaryotic‐like Ser/Thr kinases (STPKs) and has been intensively studied since, given the high interest in STPKs as possible targets for the development of new anti‐tuberculosis drugs . PknA is found together with a second kinase, PknB, in a conserved operon that also includes two genes coding for FHA domain proteins (FhaA and FhaB), a penicillin‐binding protein (PbpA), a putative cell division protein (RodA), and the only known Ser/Thr phosphatase (PstP) of the M. tuberculosis genome .…”

Mycobacterium tuberculosis Transcription Machinery: Ready To Respond to Host Attacks

“…In particular, there is a growing area of research into the roles of nucleoid-associated proteins and small RNAs (150)(151)(152)(153)(154)(155). M. tuberculosis also contains 11 serine/ threonine protein kinases (STPKs) that, like TCSs, are involved in signal transduction pathways that aid M. tuberculosis in adaptation to its environment (156 …”

Nε- and O-Acetylation in Mycobacterium tuberculosis Lineage 7 and Lineage 4 Strains: Proteins Involved in Bioenergetics, Virulence, and Antimicrobial Resistance Are Acetylated

“…86,87 Four of the 11 Mtb STPKs, PknD, PknK, PknG, and PknH, were acetylated at various residues. OpcA and Wag31 have been shown to be upregulated in INH-resistant Mtb strains; 49,88 OpcA and Wag31 are involved in peptidoglycan biosynthesis and oxidative stress responses.…”

“…These proteins are indispensable for Mtb in signal transduction mechanisms that lead to bacterial adaptation to its environment, 87 detoxification, and drug resistance 85,116 or are involved in the entry and survival of the pathogen inside macrophages. 117 Although the exact mechanism remains unknown, acetylation of enzymes involved in Mtb fitness and survival may lead to a change in the net charge of the protein, altering its stability and compartmentalization, bringing a conformational change, and/or blocking kinase substrates, and may thus modulate activity.…”