EXCEED THE SPACE PROVIDED. The long term objectives of this research remain unchanged. The goals 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. FtsZ is the ancestral homologue of eukaryotic tubulins and undergoes dynamic assembly during the cell cycle. It is the target of several endogenous inhibitors that participate in the regulation of cell division as part of the normal cell cycle or in response to DNA damage. Our recent work has shown that SulA and MinC are inhibitors of FtsZ assembly, however, they function quite differently. SulA is synthesized following DNA damage and sequesters FtsZ preventing it from assembling. In contrast, MinC is part of a sophisticated spatial regulatory system that oscillates between the poles of the cell to prevent FtsZ from assembling near the cell poles. In vitro, MinC can prevent FtsZ assembly and acts by destabilizing FtsZ filaments. In vivo MinC requires MinD to be a functional inhibitor. MinD activates MinC by recruiting it to the membrane and conferring upon it a high affinity for a septal component. Our studies have demonstrated that MinD binds to the membrane through a C-terminal amphipathic helix. We have also shown that MinE can displace MinC from a MinCD vesicle complex and stimulate the MinD ATPase releasing MinD from the vesicle. We have also shown that MinD can polymerize on vesicles causing tubulation. Our studies have also defined the sites on MinC involved in its binding to MinD and in its binding to the septum. In the present proposal we will use genetic and biochemical approaches to further define the interactions among the Min proteins and between the Min proteins and FtsZ that are necessary to regulate cell division. We will also use the knowledge gained from our study of the E. coil Min system to explore the Min system from B. subtilis and a Par protein.

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
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
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; 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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