In bacteria such as Escherichia coli, cytokinesis is orchestrated by two essential and highly conserved cytoskeletal proteins: tubulin-like FtsZ and actin-like FtsA. These proteins coassemble into a circumferential polymeric structure, called the Z ring, on the inner membrane at the site of cell division. Once assembled, the ring then recruits a large complex of other proteins to the membrane, probably distributed in individual subcomplexes. This protein machine, often called the divisome, induces synthesis of septal peptidoglycan while constricting at the leading edge of the growing septum, eventually splitting the cell into two. The machine needs to be robust, yet responsive to a variety of inputs, and is therefore overbuilt. This proposal focuses on FtsA and its interactions with FtsZ and with later divisome proteins, because recent results indicate that FtsA regulates assembly of FtsZ, in addition to its role in tethering FtsZ polymers to the membrane and recruiting later divisome components. We hypothesize that FtsA-mediated recycling of FtsZ polymers increases the number of membrane attachment sites for divisome subcomplexes, which stabilizes the machine and maximizes its flexibility. We propose to (i) elucidate how binding of ATP and ADP stimulates FtsA activity and its interaction with FtsZ;(ii) define the molecular contacts between FtsA and FtsZ subunits within FtsZ polymers;and (iii) understand how the FtsZ/FtsA complex interacts with the later divisome subcomplexes. The study of bacterial cell division is important for two reasons. First, it is a basic cellular process that needs to be understood. Second, with the current scarcity of novel antibiotics, the universal and essential process of bacterial cytokinesis is increasingly relevant as a target of antimicrobial drugs.

Public Health Relevance

This project investigates the molecular mechanism of bacterial cell division. The highly conserved proteins in the cell division apparatus represent novel targets for new therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM061074-13
Application #
8477201
Study Section
Prokaryotic Cell and Molecular Biology Study Section (PCMB)
Program Officer
Deatherage, James F
Project Start
2000-09-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
13
Fiscal Year
2013
Total Cost
$335,467
Indirect Cost
$110,964
Name
University of Texas Health Science Center Houston
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
Haeusser, Daniel P; Hoashi, Marina; Weaver, Anna et al. (2014) The Kil peptide of bacteriophage ? blocks Escherichia coli cytokinesis via ZipA-dependent inhibition of FtsZ assembly. PLoS Genet 10:e1004217
Herricks, Jennifer R; Nguyen, Diep; Margolin, William (2014) A thermosensitive defect in the ATP binding pocket of FtsA can be suppressed by allosteric changes in the dimer interface. Mol Microbiol 94:713-27
Busiek, Kimberly K; Margolin, William (2014) A role for FtsA in SPOR-independent localization of the essential Escherichia coli cell division protein FtsN. Mol Microbiol 92:1212-26
Rowlett, Veronica Wells; Margolin, William (2014) Asymmetric constriction of dividing Escherichia coli cells induced by expression of a fusion between two min proteins. J Bacteriol 196:2089-100
Eraso, Jesus M; Markillie, Lye M; Mitchell, Hugh D et al. (2014) The highly conserved MraZ protein is a transcriptional regulator in Escherichia coli. J Bacteriol 196:2053-66
Hu, Bo; Margolin, William; Molineux, Ian J et al. (2013) The bacteriophage t7 virion undergoes extensive structural remodeling during infection. Science 339:576-9
Wells, Veronica L; Margolin, William (2012) A new slant to the Z ring and bacterial cell branch formation. Mol Microbiol 84:199-202
Liu, Jun; Chen, Cheng-Yen; Shiomi, Daisuke et al. (2011) Visualization of bacteriophage P1 infection by cryo-electron tomography of tiny Escherichia coli. Virology 417:304-11
Busiek, Kimberly K; Margolin, William (2011) Split decision: a thaumarchaeon encoding both FtsZ and Cdv cell division proteins chooses Cdv for cytokinesis. Mol Microbiol 82:535-8
Tonthat, Nam Ky; Arold, Stefan T; Pickering, Brian F et al. (2011) Molecular mechanism by which the nucleoid occlusion factor, SlmA, keeps cytokinesis in check. EMBO J 30:154-64

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