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Dynamic instability-driven centering/segregating mechanism in bacteria.

ABSTRACT: All cells require the ability to process spatial information to properly position intracellular molecules. Many protein complexes and DNA molecules are actively positioned either at the cell midpoint or cell poles, but the processes which drive intracellular positioning are still poorly understood. Using computational modeling we propose a bimodal centering/segregation mechanism in bacteria which is driven by the dynamic instability of polymerizing filaments, which grow and shrink with regularity. Modeled cell centering via dynamically unstable filaments is confirmed experimentally via in vivo time-lapse, colocalization measurements of a model system of clustered plasmid-DNA centered by the dynamically unstable actin-like protein filaments Alp7A in Bacillus subtilis. Generalizing to any cylindrical cell, we find strong cell-length dependence in the centering ability of dynamically unstable filaments, culminating in pole positioning when cell length decreases significantly below the theoretically predicted average filament length. Modeling dynamic instability-driven positioning mechanisms from multiple anisotropic in vivo systems demonstrates that dynamically unstable filaments are a general mechanism for both midcell and cell-pole (segregation) positioning, and that desired positioning is preferentially selected in vivo by intrinsic filament polymerization rates and number.

SUBMITTER: Drew KR

PROVIDER: S-EPMC3131362 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Dynamic instability-driven centering/segregating mechanism in bacteria.

Drew Kirstin R Purdy KR Pogliano Joe J

Proceedings of the National Academy of Sciences of the United States of America 20110617 27

All cells require the ability to process spatial information to properly position intracellular molecules. Many protein complexes and DNA molecules are actively positioned either at the cell midpoint or cell poles, but the processes which drive intracellular positioning are still poorly understood. Using computational modeling we propose a bimodal centering/segregation mechanism in bacteria which is driven by the dynamic instability of polymerizing filaments, which grow and shrink with regularit ...[more]

PMID: 21685333

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Project description:A systems-level mathematical model is presented that describes the effects of inhibiting the enzyme 5α-reductase (5aR) on the ventral prostate of the adult male rat under chronic administration of the 5aR inhibitor, finasteride. 5aR is essential for androgen regulation in males, both in normal conditions and disease states. The hormone kinetics and downstream effects on reproductive organs associated with perturbing androgen regulation are complex and not necessarily intuitive. Inhibition of 5aR decreases the metabolism of testosterone (T) to the potent androgen 5α-dihydrotestosterone (DHT). This results in decreased cell proliferation, fluid production and 5aR expression as well as increased apoptosis in the ventral prostate. These regulatory changes collectively result in decreased prostate size and function, which can be beneficial to men suffering from benign prostatic hyperplasia (BPH) and could play a role in prostate cancer. There are two distinct isoforms of 5aR in male humans and rats, and thus developing a 5aR inhibitor is a challenging pursuit. Several inhibitors are on the market for treatment of BPH, including finasteride and dutasteride. In this effort, comparisons of simulated vs. experimental T and DHT levels and prostate size are depicted, demonstrating the model accurately described an approximate 77% decrease in prostate size and nearly complete depletion of prostatic DHT following 21 days of daily finasteride dosing in rats. This implies T alone is not capable of maintaining a normal prostate size. Further model analysis suggests the possibility of alternative dosing strategies resulting in similar or greater effects on prostate size, due to complex kinetics between T, DHT and gene occupancy. With appropriate scaling and parameterization for humans, this model provides a multiscale modeling platform for drug discovery teams to test and generate hypotheses about drugging strategies for indications like BPH and prostate cancer, such as compound binding properties, dosing regimens, and target validation.

Dataset Information

Dynamic instability-driven centering/segregating mechanism in bacteria.

Publications

Dynamic instability-driven centering/segregating mechanism in bacteria.

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