32 research outputs found
Simulations of tubulin sheet polymers as possible structural intermediates in microtubule assembly
The microtubule assembly process has been extensively studied, but the
underlying molecular mechanism remains poorly understood. The structure of an
artificially generated sheet polymer that alternates two types of lateral
contacts and that directly converts into microtubules, has been proposed to
correspond to the intermediate sheet structure observed during microtubule
assembly. We have studied the self-assembly process of GMPCPP tubulins into
sheet and microtubule structures using thermodynamic analysis and stochastic
simulations. With the novel assumptions that tubulins can laterally interact in
two different forms, and allosterically affect neighboring lateral
interactions, we can explain existing experimental observations. At low
temperature, the allosteric effect results in the observed sheet structure with
alternating lateral interactions as the thermodynamically most stable form. At
normal microtubule assembly temperature, our work indicates that a class of
sheet structures resembling those observed at low temperature is transiently
trapped as an intermediate during the assembly process. This work may shed
light on the tubulin molecular interactions, and the role of sheet formation
during microtubule assembly.Comment: 43 pages, 13 figures. Submitted; PLoS ONE 200
Network Topologies and Dynamics Leading to Endotoxin Tolerance and Priming in Innate Immune Cells
The innate immune system, acting as the first line of host defense, senses
and adapts to foreign challenges through complex intracellular and
intercellular signaling networks. Endotoxin tolerance and priming elicited by
macrophages are classic examples of the complex adaptation of innate immune
cells. Upon repetitive exposures to different doses of bacterial endotoxin
(lipopolysaccharide) or other stimulants, macrophages show either suppressed or
augmented inflammatory responses compared to a single exposure to the
stimulant. Endotoxin tolerance and priming are critically involved in both
immune homeostasis and the pathogenesis of diverse inflammatory diseases.
However, the underlying molecular mechanisms are not well understood. By means
of a computational search through the parameter space of a coarse-grained
three-node network with a two-stage Metropolis sampling approach, we enumerated
all the network topologies that can generate priming or tolerance. We
discovered three major mechanisms for priming (pathway synergy, suppressor
deactivation, activator induction) and one for tolerance (inhibitor
persistence). These results not only explain existing experimental
observations, but also reveal intriguing test scenarios for future experimental
studies to clarify mechanisms of endotoxin priming and tolerance.Comment: 15 pages, 8 figures, submitte