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Review
. 2011 Mar;75(1):192-212.
doi: 10.1128/MMBR.00042-10.

Eukaryote-like serine/threonine kinases and phosphatases in bacteria

Sandro F F Pereira  1 , Lindsie Goss, Jonathan Dworkin
Affiliations
Review

Eukaryote-like serine/threonine kinases and phosphatases in bacteria

Sandro F F Pereira et al. Microbiol Mol Biol Rev. 2011 Mar.

Abstract

Genomic studies have revealed the presence of Ser/Thr kinases and phosphatases in many bacterial species, although their physiological roles have largely been unclear. Here we review bacterial Ser/Thr kinases (eSTKs) that show homology in their catalytic domains to eukaryotic Ser/Thr kinases and their partner phosphatases (eSTPs) that are homologous to eukaryotic phosphatases. We first discuss insights into the enzymatic mechanism of eSTK activation derived from structural studies on both the ligand-binding and catalytic domains. We then turn our attention to the identified substrates of eSTKs and eSTPs for a number of species and to the implications of these findings for understanding their physiological roles in these organisms.

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Figures

FIG. 1.
FIG. 1.
Structure of the Ser/Thr kinase catalytic domain. (A) Crystal structure of the mouse PKA catalytic domain in complex with an ATP molecule and an inhibitor peptide (Protein Data Bank [PDB] accession number 1ATP). The PKA N-terminal lobe is shown in gray, and the C-terminal lobe is shown in blue. ATP is represented as sticks, with two manganese ions shown as spheres, and the inhibitor peptide is shown as a red line. (B) Superimposition of tertiary structures of PKA and the M. tuberculosis eSTK PknB (PDB accession number 1MRU). PKA is shown in blue, and PknB is shown in yellow. (C) The regulatory elements that comprise the catalytic cleft formed between the N- and C-terminal lobes of the Ser/Thr kinase catalytic domain are indicated in the structure of PKA as follows: green, P loop; yellow, catalytic loop with the catalytic Asp residue; magenta, magnesium-binding loop; orange, activation loop with the phosphorylated Thr residue; and cyan, P+1 loop. ATP is represented as sticks, with two manganese ions shown as spheres, and the inhibitor peptide is shown as a red line. (D) Primary sequence alignment between the PKA (residues 33 to 283) and PknB (residues 1 to 266) catalytic domains. The N- and C-terminal lobes of PKA are shown in gray and blue, respectively. Conserved motifs are shown in boxes, and the invariant residues are depicted in black. Other important residues are highlighted and/or shown in bold. Red and orange asterisks indicate the catalytic Asp and phosphorylated Thr residues, respectively.
FIG. 2.
FIG. 2.
Dimerization interfaces involved in bacterial eSTK activation. (A) Back-to-back dimer revealed in the crystal structure of the M. tuberculosis PknB kinase domain (PDB accession number 1MRU). Two PknB monomers interact through a dimerization interface located in the back sides of the N-terminal lobes (130, 195). (B) Asymmetric front-to-front dimer found in the cocrystal of a mutant PknB kinase domain in complex with an ATP competitive inhibitor (PDB accession number 3F69). This structure resembles an activation complex involving the contact between the αG helixes of two monomers (103). One of the monomers (blue) shows an ordered activation loop (red), characteristic of the active state, whereas the other monomer (green) shows a disordered activation loop (represented by a dashed line). (C) Dimerization of two M. tuberculosis PknG kinase monomers. The complete structure of PknG is shown (PDB accession number 2PZI), including the N-terminal rubredoxin domain (RD) and the C-terminal tetratricopeptide repeat domain (TPRD) that surround the kinase catalytic domain (KD). In contrast with the case for PknB, dimerization of PknG occurs through interaction between the TPRDs of two monomers (153).
FIG. 3.
FIG. 3.
Activation model for eSTKs. M. tuberculosis PknB was chosen for the purpose of illustrating the hypothesized eSTK activation pathways. (A) In the presence of a ligand, two or more PknB monomers bind to a single ligand molecule through their extracellular domains. This brings the intracellular catalytic domains closer, resulting in the formation of a symmetric back-to-back dimer and in the consequent activation of the kinases by autophosphorylation (see text for details). (B) An activated kinase can directly phosphorylate a downstream protein target or activate a soluble kinase through the formation of an asymmetric front-to-front dimer, which will then phosphorylate downstream targets as part of a signaling pathway.
FIG. 4.
FIG. 4.
Structures of M. tuberculosis PknB and PknG sensor domains. (A) The extracellular domain of M. tuberculosis PknB is composed of four PASTA repeats organized linearly (PDB accession number 2KUI) (12). (B) The highly symmetric six-bladed β propeller formed by the extracellular domain of M. tuberculosis PknG kinase (PDB accession number 1RWI) (56). The PknB catalytic domain is shown to represent the intracellular catalytic kinase domain.
FIG. 5.
FIG. 5.
Regulation of the developmental cycle of Myxococcus xanthus. The M. xanthus transcriptional activator MrpC controls the expression of fruA, which encodes a major regulator of fruiting body formation and sporulation. MrpC is itself under dual regulation of an eSTK signaling cascade and a TCS. During vegetative growth, phosphorylation by the eSTK PknB14/8 signaling cascade decreases MrpC's affinity for the fruA promoter and its own promoter. In response to starvation signals, the MrpA/MrpB TCS activates the transcription of mrpC as well as itself, leading to the expression of fruA and the consequent developmental commitment.
FIG. 6.
FIG. 6.
Ser/Thr phosphatase structures. (A) Primary sequence alignment of human PP2C (residues 1 to 299) and PphA (residues 1 to 241) catalytic domains. Conserved amino acids are indicated in bold, and those that also form part of the metal-binding pocket are shown in red. Motifs 1 to 5, 5a, 5b, and 6 to 11, as defined by Bork et al. (19), are indicated in boxes. (B) Crystal structure of the human PP2C structure (PDB accession number 1A6Q). The β-sandwich is represented in yellow, α-helices are represented in blue, the large irregular loop is shown in red, and two manganese ions are shown in gray. His62 (orange) is predicted to be a general acid. The C-terminal domain (α7, α8, and α9) is characteristic of mammalian PP2C and is absent from prokaryotic family members. (C) Crystal structure of the Thermosynechococcus elongatus eSTP PphA (PDB accession number 2J86). The β-sandwich is shown in yellow, the α-helices are shown in blue, the three magnesium ions are shown in gray, and the large irregular loop is shown in red. The flap subdomain (red) appears flexible and is thought to be involved in substrate binding and catalytic activity. Instead of His62, Met62 (orange) occupies the homologous position.
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