| Structural highlights
Function
PKNB_MYCTU Key component of a signal transduction pathway that regulates cell growth and cell division via phosphorylation of target proteins such as GarA, GlmU, PapA5, PbpA, FhaB (Rv0019c), FhaA (Rv0020c), MviN, PstP, EmbR, Rv1422, Rv1747 and RseA. Shows a strong preference for Thr versus Ser as the phosphoacceptor.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]
Publication Abstract from PubMed
The essential Mycobacterium tuberculosis Ser/Thr protein kinase (STPK), PknB, plays a key role in regulating growth and division, but the structural basis of activation has not been defined. Here, we provide biochemical and structural evidence that dimerization through the kinase-domain (KD) N-lobe activates PknB by an allosteric mechanism. Promoting KD pairing using a small-molecule dimerizer stimulates the unphosphorylated kinase, and substitutions that disrupt N-lobe pairing decrease phosphorylation activity in vitro and in vivo. Multiple crystal structures of two monomeric PknB KD mutants in complex with nucleotide reveal diverse inactive conformations that contain large active-site distortions that propagate > 30 A from the mutation site. These results define flexible, inactive structures of a monomeric bacterial receptor KD and show how "back-to-back" N-lobe dimerization stabilizes the active KD conformation. This general mechanism of bacterial receptor STPK activation affords insights into the regulation of homologous eukaryotic kinases that form structurally similar dimers.
Allosteric activation mechanism of the Mycobacterium tuberculosis receptor Ser/Thr protein kinase, PknB.,Lombana TN, Echols N, Good MC, Thomsen ND, Ng HL, Greenstein AE, Falick AM, King DS, Alber T Structure. 2010 Dec 8;18(12):1667-77. doi: 10.1016/j.str.2010.09.019. PMID:21134645[12]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kang CM, Abbott DW, Park ST, Dascher CC, Cantley LC, Husson RN. The Mycobacterium tuberculosis serine/threonine kinases PknA and PknB: substrate identification and regulation of cell shape. Genes Dev. 2005 Jul 15;19(14):1692-704. Epub 2005 Jun 28. PMID:15985609 doi:http://dx.doi.org/10.1101/gad.1311105
- ↑ Villarino A, Duran R, Wehenkel A, Fernandez P, England P, Brodin P, Cole ST, Zimny-Arndt U, Jungblut PR, Cervenansky C, Alzari PM. Proteomic identification of M. tuberculosis protein kinase substrates: PknB recruits GarA, a FHA domain-containing protein, through activation loop-mediated interactions. J Mol Biol. 2005 Jul 29;350(5):953-63. PMID:15978616 doi:http://dx.doi.org/10.1016/j.jmb.2005.05.049
- ↑ Grundner C, Gay LM, Alber T. Mycobacterium tuberculosis serine/threonine kinases PknB, PknD, PknE, and PknF phosphorylate multiple FHA domains. Protein Sci. 2005 Jul;14(7):1918-21. PMID:15987910 doi:http://dx.doi.org/10.1110/ps.051413405
- ↑ Sharma K, Gupta M, Krupa A, Srinivasan N, Singh Y. EmbR, a regulatory protein with ATPase activity, is a substrate of multiple serine/threonine kinases and phosphatase in Mycobacterium tuberculosis. FEBS J. 2006 Jun;273(12):2711-21. PMID:16817899 doi:http://dx.doi.org/10.1111/j.1742-4658.2006.05289.x
- ↑ Fernandez P, Saint-Joanis B, Barilone N, Jackson M, Gicquel B, Cole ST, Alzari PM. The Ser/Thr protein kinase PknB is essential for sustaining mycobacterial growth. J Bacteriol. 2006 Nov;188(22):7778-84. Epub 2006 Sep 15. PMID:16980473 doi:http://dx.doi.org/10.1128/JB.00963-06
- ↑ Dasgupta A, Datta P, Kundu M, Basu J. The serine/threonine kinase PknB of Mycobacterium tuberculosis phosphorylates PBPA, a penicillin-binding protein required for cell division. Microbiology. 2006 Feb;152(Pt 2):493-504. PMID:16436437 doi:http://dx.doi.org/152/2/493
- ↑ Gupta M, Sajid A, Arora G, Tandon V, Singh Y. Forkhead-associated domain-containing protein Rv0019c and polyketide-associated protein PapA5, from substrates of serine/threonine protein kinase PknB to interacting proteins of Mycobacterium tuberculosis. J Biol Chem. 2009 Dec 11;284(50):34723-34. Epub 2009 Oct 13. PMID:19826007 doi:http://dx.doi.org/M109.058834
- ↑ Parikh A, Verma SK, Khan S, Prakash B, Nandicoori VK. PknB-mediated phosphorylation of a novel substrate, N-acetylglucosamine-1-phosphate uridyltransferase, modulates its acetyltransferase activity. J Mol Biol. 2009 Feb 20;386(2):451-64. Epub 2008 Dec 24. PMID:19121323 doi:10.1016/j.jmb.2008.12.031
- ↑ Barik S, Sureka K, Mukherjee P, Basu J, Kundu M. RseA, the SigE specific anti-sigma factor of Mycobacterium tuberculosis, is inactivated by phosphorylation-dependent ClpC1P2 proteolysis. Mol Microbiol. 2010 Feb;75(3):592-606. doi: 10.1111/j.1365-2958.2009.07008.x., Epub 2009 Dec 16. PMID:20025669 doi:http://dx.doi.org/10.1111/j.1365-2958.2009.07008.x
- ↑ Sajid A, Arora G, Gupta M, Upadhyay S, Nandicoori VK, Singh Y. Phosphorylation of Mycobacterium tuberculosis Ser/Thr phosphatase by PknA and PknB. PLoS One. 2011 Mar 9;6(3):e17871. doi: 10.1371/journal.pone.0017871. PMID:21423706 doi:http://dx.doi.org/10.1371/journal.pone.0017871
- ↑ Gee CL, Papavinasasundaram KG, Blair SR, Baer CE, Falick AM, King DS, Griffin JE, Venghatakrishnan H, Zukauskas A, Wei JR, Dhiman RK, Crick DC, Rubin EJ, Sassetti CM, Alber T. A phosphorylated pseudokinase complex controls cell wall synthesis in mycobacteria. Sci Signal. 2012 Jan 24;5(208):ra7. PMID:22275220 doi:10.1126/scisignal.2002525
- ↑ Lombana TN, Echols N, Good MC, Thomsen ND, Ng HL, Greenstein AE, Falick AM, King DS, Alber T. Allosteric activation mechanism of the Mycobacterium tuberculosis receptor Ser/Thr protein kinase, PknB. Structure. 2010 Dec 8;18(12):1667-77. doi: 10.1016/j.str.2010.09.019. PMID:21134645 doi:http://dx.doi.org/10.1016/j.str.2010.09.019
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