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Chapter 33 : Serine/Threonine Protein Kinases

Authors: Sladjana Prisic1, Robert N. Husson2
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Affiliations: 1: Division of Infectious Diseases, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Ave., Boston, MA 02115; 2: Division of Infectious Diseases, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Ave., Boston, MA 02115
Content Type: Monograph
Publication Year: 2014

Category: Microbial Genetics and Molecular Biology

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Abstract:

Signal transduction is an essential activity of all living cells. Broadly defined, signal transduction is the sensing of a signal or input and its conversion into an output or response that alters cell physiology. The sensor is the molecule or domain of a molecule (typically a protein) that senses the signal. The transducer is the molecule or domain that converts the signal into a response. Most commonly, signal transduction refers to the sensing of an extracellular signal that is transduced across the cytoplasmic membrane and converted into an intracellular response. Thus, signal transduction is critical for cellular adaptation to changes in the extracellular environment. In the case of bacterial pathogens, including , these adaptive responses allow growth and/or survival in the environments encountered by the pathogen during the course of infection in the human host.

Citation: Prisic S, Husson R. 2014. Serine/Threonine Protein Kinases, p 681-708. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0006-2013
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Mycobacterium tuberculosis Serine/Threonine Protein Kinases
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Citation: Prisic S, Husson R. 2014. Serine/Threonine Protein Kinases, p 681-708. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0006-2013
/content/10.1128/9781555818845.chap33.fig33-1
Figure 1
Domain organization of STPKs from Domains were predicted using the SMART algorithm ( ). Kinase domains are shown as green boxes, transmembrane portions are in blue, and some known extracellular domains are in light red.
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Figure 1

Domain organization of STPKs from Domains were predicted using the SMART algorithm ( ). Kinase domains are shown as green boxes, transmembrane portions are in blue, and some known extracellular domains are in light red.

Citation: Prisic S, Husson R. 2014. Serine/Threonine Protein Kinases, p 681-708. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0006-2013
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Figure 2
Sequence alignment of STPKs from Kinase domains predicted by the SMART algorithm (see Fig. 1 ) were aligned and grouped using AlignX software (Life Technologies). Human Clk1 kinase is also included for comparison. Major features are noted. Selected conserved residues are labeled with the following symbols (residue numbers from PknB): *, Lys40; #, Glu59; &, Asp138; $, Asn143; %, Asp156; p, major phosphorylation sites in the activation loop.
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Figure 2

Sequence alignment of STPKs from Kinase domains predicted by the SMART algorithm (see Fig. 1 ) were aligned and grouped using AlignX software (Life Technologies). Human Clk1 kinase is also included for comparison. Major features are noted. Selected conserved residues are labeled with the following symbols (residue numbers from PknB): *, Lys40; #, Glu59; &, Asp138; $, Asn143; %, Asp156; p, major phosphorylation sites in the activation loop.

Citation: Prisic S, Husson R. 2014. Serine/Threonine Protein Kinases, p 681-708. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0006-2013
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Figure 3
Dendrogram of KDs of STPKs. KDs identified by the SMART algorithm were aligned and grouped using the AlignX software (Life Technologies). Human Clk1 kinase is also included for comparison. Distance scores as given by AlignX are shown in parentheses.
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Figure 3

Dendrogram of KDs of STPKs. KDs identified by the SMART algorithm were aligned and grouped using the AlignX software (Life Technologies). Human Clk1 kinase is also included for comparison. Distance scores as given by AlignX are shown in parentheses.

Citation: Prisic S, Husson R. 2014. Serine/Threonine Protein Kinases, p 681-708. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0006-2013
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Figure 4
Overview of the STPK’s KD. Major features of the PknB KD (1MRU_B): N-terminal (upper) and C-terminal (lower) lobes are labeled. The ATP analog is in blue, and two Mg ions are in green. Overlap of PknB (green) and Clk1 (magenta). Clk1 was a top hit when the PknB structure was used to search similar three-dimensional structures using the NCBI VAST program. For clarity, residues 298 to 319 and 395 to 443 in Clk1 that are absent in STPKs (see Fig. 2 ) are truncated in Clk1. PknB (1MRU_B), PknE (2H34_B), PknG (2PZI_A), and Clk1 (1Z57). α-Helix is in red, β-sheet is in yellow. Figures were made using PyMOL (Schrödinger) and POV-Ray (povray.org).
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Figure 4

Overview of the STPK’s KD. Major features of the PknB KD (1MRU_B): N-terminal (upper) and C-terminal (lower) lobes are labeled. The ATP analog is in blue, and two Mg ions are in green. Overlap of PknB (green) and Clk1 (magenta). Clk1 was a top hit when the PknB structure was used to search similar three-dimensional structures using the NCBI VAST program. For clarity, residues 298 to 319 and 395 to 443 in Clk1 that are absent in STPKs (see Fig. 2 ) are truncated in Clk1. PknB (1MRU_B), PknE (2H34_B), PknG (2PZI_A), and Clk1 (1Z57). α-Helix is in red, β-sheet is in yellow. Figures were made using PyMOL (Schrödinger) and POV-Ray (povray.org).

Citation: Prisic S, Husson R. 2014. Serine/Threonine Protein Kinases, p 681-708. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0006-2013
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Figure 5
Active site of PknB KD. Overlap of “closed” PknB KD (1MRU_B) in green and “open” apo-PknE-KD (2H34) in blue, with the PknE C helix labeled in red. PknB active site (1MRU_B) P loop (GFGGMS), magenta; Mg, red balls; ATPγS, yellow; C-helix, green (Glu59-green); Lys40, aqua; catalytic loop, red (Asp138-orange, Asn143-red); DFG motif, purple (Asp156-purple). Figures were made using PyMOL (Schrödinger) and POV-Ray (povray.org).
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Figure 5

Active site of PknB KD. Overlap of “closed” PknB KD (1MRU_B) in green and “open” apo-PknE-KD (2H34) in blue, with the PknE C helix labeled in red. PknB active site (1MRU_B) P loop (GFGGMS), magenta; Mg, red balls; ATPγS, yellow; C-helix, green (Glu59-green); Lys40, aqua; catalytic loop, red (Asp138-orange, Asn143-red); DFG motif, purple (Asp156-purple). Figures were made using PyMOL (Schrödinger) and POV-Ray (povray.org).

Citation: Prisic S, Husson R. 2014. Serine/Threonine Protein Kinases, p 681-708. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0006-2013
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Figure 6
Back-to-back dimerization of KDs. PknB-KD dimer showing “back-to-back” interaction. Overlap of PknB-KD in active form (1MRU_B-blue) and conformations of the PknB-KD L33D mutant that perturbs the dimer interface (3ORK, yellow; 3ORI_A, red; 3ORL, green). The C helix is shown in ribbon, while the rest of the structure is shown in wire. C helix from the PknB structures in panel B magnified to highlight differences in the position of Glu59. Figures were made using PyMOL (Schrödinger) and POV-Ray (povray.org).
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Figure 6

Back-to-back dimerization of KDs. PknB-KD dimer showing “back-to-back” interaction. Overlap of PknB-KD in active form (1MRU_B-blue) and conformations of the PknB-KD L33D mutant that perturbs the dimer interface (3ORK, yellow; 3ORI_A, red; 3ORL, green). The C helix is shown in ribbon, while the rest of the structure is shown in wire. C helix from the PknB structures in panel B magnified to highlight differences in the position of Glu59. Figures were made using PyMOL (Schrödinger) and POV-Ray (povray.org).

Citation: Prisic S, Husson R. 2014. Serine/Threonine Protein Kinases, p 681-708. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0006-2013
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Figure 7
Distinct modes of monomer interaction in dimers of PknB versus PknG “Front-to-front” dimer of mutant PknB KD (3F69) in complex with Kt5720 inhibitor (yellow). The “substrate” subunit (magenta) has most of its activation loop disordered (red), while the “enzyme” subunit (blue) has a well-defined activation loop (orange) with visible phosphorylated Thr171 (green). Structure of PknG (2PZI) in complex with inhibitor Ax20017 (magenta). Three domains: rubredoxin (yellow), KD (green), and TPR domain (red) are shown only in one subunit. The second subunit is depicted in gray. Figures were made in PyMOL (Schrödinger) and POV-Ray (povray.org).
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Figure 7

Distinct modes of monomer interaction in dimers of PknB versus PknG “Front-to-front” dimer of mutant PknB KD (3F69) in complex with Kt5720 inhibitor (yellow). The “substrate” subunit (magenta) has most of its activation loop disordered (red), while the “enzyme” subunit (blue) has a well-defined activation loop (orange) with visible phosphorylated Thr171 (green). Structure of PknG (2PZI) in complex with inhibitor Ax20017 (magenta). Three domains: rubredoxin (yellow), KD (green), and TPR domain (red) are shown only in one subunit. The second subunit is depicted in gray. Figures were made in PyMOL (Schrödinger) and POV-Ray (povray.org).

Citation: Prisic S, Husson R. 2014. Serine/Threonine Protein Kinases, p 681-708. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0006-2013
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Figure 8
phosphoproteome. Phosphoproteins were identified in all functional categories of proteins ( ).
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Figure 8

phosphoproteome. Phosphoproteins were identified in all functional categories of proteins ( ).

Citation: Prisic S, Husson R. 2014. Serine/Threonine Protein Kinases, p 681-708. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0006-2013
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Tables

Mycobacterium tuberculosis Serine/Threonine Protein Kinases
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Citation: Prisic S, Husson R. 2014. Serine/Threonine Protein Kinases, p 681-708. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0006-2013
/content/10.1128/9781555818845.chap33.tab33-1
Table 1
Closest orthologs of STPKs
Generic image for table
Table 1

Closest orthologs of STPKs

Citation: Prisic S, Husson R. 2014. Serine/Threonine Protein Kinases, p 681-708. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0006-2013
/content/10.1128/9781555818845.chap33.tab33-2
Table 2
Structures of STPKs available in the Research Collaboratory for Structural Bioinformatics (RCSB) Protein Database (PDB)
Generic image for table
Table 2

Structures of STPKs available in the Research Collaboratory for Structural Bioinformatics (RCSB) Protein Database (PDB)

Citation: Prisic S, Husson R. 2014. Serine/Threonine Protein Kinases, p 681-708. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0006-2013
/content/10.1128/9781555818845.chap33.tab33-3
Table 3
Phosphorylated proteins in in addition to those identified in the phosphoproteomic study of Prisic et al. ( )
Generic image for table
Table 3

Phosphorylated proteins in in addition to those identified in the phosphoproteomic study of Prisic et al. ( )

Citation: Prisic S, Husson R. 2014. Serine/Threonine Protein Kinases, p 681-708. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0006-2013

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