The long term objectives of this research are to determine the molecular mechanisms involved in bacterial cell division and the underlying spatial and temporal regulatory mechanisms. Our efforts have focused on the FtsZ protein which assembles into a cytoskeletal ring that recruits other proteins to the division site and directs cell division in bacteria. Recent work has shown that FtsZ is a structural and functional homologue of the eukaryotic cytoskeletal protein tubulin. Like tubulin FtsZ undergoes dynamic assembly that is regulated by GTPhydrolysis. Also, FtsZ is a target of several inhibitors that regulate cell division in bacteria. Our recent work has shown that SulA and MinC are inhibitors of FtsZ assembly. SulA is induced in response to DNAdamage and MinC is part of the division site selection system. In the present proposal biochemical and genetic studies are designed to determine the mechanism of action of these inhibitors. At present SulA is thought to sequester FtsZ monomers and MinC is thought to destabilize FtsZ polymers. Our present studies should further define the interaction between FtsZ and these inhibitors to test the postulated mechanisms. Also, several aspects of MinC's mode of action will be investigated including it's interaction with MinD and MinE, which cause it to oscillate between the poles of the cell. In addition, studying the various mutant FtsZs should reveal additional aspects of FtsZ assembly. The present proposal will also examine the interaction between FtsZ and ZipA and FtsA. Genetic and biochemical experiments are proposed to investigate the interacting surfaces between these proteins and the role of these proteins in FtsZ assembly. FtsZ mutants that will be isolated will serve as controls for in vitro experiments. Additional ftsZ (Ts)mutations will be isolated and used to look for suppressors in an attempt to find other proteins that regulate FtsZ assembly. Research over the past fewyears has shown that FtsZ is a universal feature of bacterial cell division. It has great similarity to tubulin but is also quite distinct. As a result it should prove to be a useful, novel target for antimicrobial therapy.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Deatherage, James F
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University of Kansas
Schools of Medicine
Kansas City
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Du, Shishen; Pichoff, Sebastien; Kruse, Karsten et al. (2018) FtsZ filaments have the opposite kinetic polarity of microtubules. Proc Natl Acad Sci U S A 115:10768-10773
Du, Shishen; Lutkenhaus, Joe (2017) Assembly and activation of the Escherichia coli divisome. Mol Microbiol 105:177-187
Park, Kyung-Tae; Villar, Maria T; Artigues, Antonio et al. (2017) MinE conformational dynamics regulate membrane binding, MinD interaction, and Min oscillation. Proc Natl Acad Sci U S A 114:7497-7504
Pichoff, Sebastien; Du, Shishen; Lutkenhaus, Joe (2015) The bypass of ZipA by overexpression of FtsN requires a previously unknown conserved FtsN motif essential for FtsA-FtsN interaction supporting a model in which FtsA monomers recruit late cell division proteins to the Z ring. Mol Microbiol 95:971-87
Du, Shishen; Park, Kyung-Tae; Lutkenhaus, Joe (2015) Oligomerization of FtsZ converts the FtsZ tail motif (conserved carboxy-terminal peptide) into a multivalent ligand with high avidity for partners ZipA and SlmA. Mol Microbiol 95:173-88
Park, Kyung-Tae; Du, Shishen; Lutkenhaus, Joe (2015) MinC/MinD copolymers are not required for Min function. Mol Microbiol 98:895-909
Du, Shishen; Lutkenhaus, Joe (2014) SlmA antagonism of FtsZ assembly employs a two-pronged mechanism like MinCD. PLoS Genet 10:e1004460
Du, Shishen; Lutkenhaus, Joe (2012) MipZ: one for the pole, two for the DNA. Mol Cell 46:239-40
Park, Kyung-Tae; Wu, Wei; Lovell, Scott et al. (2012) Mechanism of the asymmetric activation of the MinD ATPase by MinE. Mol Microbiol 85:271-81
Lutkenhaus, Joe (2012) The ParA/MinD family puts things in their place. Trends Microbiol 20:411-8

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