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1.  Competition and compensation 
Bioarchitecture  2012;2(5):171-174.
Stereocilia are actin protrusions with remarkably well-defined lengths and organization. A flurry of recent papers has reported multiple myosin motor proteins involved in regulating stereocilia structures by transporting actin-regulatory cargo to the tips of stereocilia.1-13 In our recent paper, we show that two paralogous class 3 myosins — Myo3a and Myo3b — both transport the actin-regulatory protein Espin 1 (Esp1) to stereocilia and filopodia tips in a remarkably similar, albeit non-identical fashion.1 Here we present experimental and computational data that suggests that subtle differences between these two proteins’ biophysical and biochemical properties can help us understand how these myosin species target and regulate the lengths of actin protrusions.
doi:10.4161/bioa.21733
PMCID: PMC3696061  PMID: 22954581
myosin; actin; filopodia; cytoskeleton; motor proteins; stereocilia; deafness
2.  Sarcomeric Pattern Formation by Actin Cluster Coalescence 
PLoS Computational Biology  2012;8(6):e1002544.
Contractile function of striated muscle cells depends crucially on the almost crystalline order of actin and myosin filaments in myofibrils, but the physical mechanisms that lead to myofibril assembly remains ill-defined. Passive diffusive sorting of actin filaments into sarcomeric order is kinetically impossible, suggesting a pivotal role of active processes in sarcomeric pattern formation. Using a one-dimensional computational model of an initially unstriated actin bundle, we show that actin filament treadmilling in the presence of processive plus-end crosslinking provides a simple and robust mechanism for the polarity sorting of actin filaments as well as for the correct localization of myosin filaments. We propose that the coalescence of crosslinked actin clusters could be key for sarcomeric pattern formation. In our simulations, sarcomere spacing is set by filament length prompting tight length control already at early stages of pattern formation. The proposed mechanism could be generic and apply both to premyofibrils and nascent myofibrils in developing muscle cells as well as possibly to striated stress-fibers in non-muscle cells.
Author Summary
Muscle contraction driving voluntary movements and the beating of the heart relies on the contraction of highly regular bundles of actin and myosin filaments, which share a periodic, sarcomeric pattern. We know little about the mechanisms by which these ‘biological crystals’ are assembled and it is a general question how order on a scale of 100 micrometers can emerge from the interactions of micrometer-sized building blocks, such as actin and myosin filaments. In our paper, we consider a computational model for a bundle of actin filaments and discuss physical mechanisms by which periodic order emerges spontaneously. Mutual crosslinking of actin filaments results in the formation and coalescence of growing actin clusters. Active elongation and shrinkage dynamics of actin filaments generates polymerization forces and causes local actin flow that can act like a conveyor belt to sort myosin filaments in place.
doi:10.1371/journal.pcbi.1002544
PMCID: PMC3369942  PMID: 22685394
3.  Releasing the brakes while hanging on 
Bioarchitecture  2012;2(1):11-14.
Actin polymerization plays a major role in many cellular processes, including cell motility, vesicle trafficking, and pathogen propulsion. The transformation of the (protrusive) polymerization forces into directed motion requires that the growing filaments are positioned next to the surface. This is achieved by localization of surface actin nucleators (WASP), which then activate Arp2/3 complex to form new actin branches. Yet, the same surface-bound WASP molecule which initiates the nucleation of new actin branches, also inherently prevents the translation of the polymerization forces into motion, essentially because the WASP molecule has to be in contact with the network during the formation of the new branch. In our recent paper we show that cortactin relaxes this internal inhibition by enhancing the release of WASP-VCA molecule from the new branching site after nucleation is initiated. We show that this enhanced release has two major effects; it increases the turnover rate of branching per WASP molecule, and it decreases the friction-like force caused by the binding of the moving surface with respect to the growing actin network.
PMCID: PMC3383711  PMID: 22754622
Arp2/3 complex; WASP-VCA; actin-based motility; cortactin; friction-like force; propulsion velocity
4.  Theoretical Model for Cellular Shapes Driven by Protrusive and Adhesive Forces 
PLoS Computational Biology  2011;7(5):e1001127.
The forces that arise from the actin cytoskeleton play a crucial role in determining the cell shape. These include protrusive forces due to actin polymerization and adhesion to the external matrix. We present here a theoretical model for the cellular shapes resulting from the feedback between the membrane shape and the forces acting on the membrane, mediated by curvature-sensitive membrane complexes of a convex shape. In previous theoretical studies we have investigated the regimes of linear instability where spontaneous formation of cellular protrusions is initiated. Here we calculate the evolution of a two dimensional cell contour beyond the linear regime and determine the final steady-state shapes arising within the model. We find that shapes driven by adhesion or by actin polymerization (lamellipodia) have very different morphologies, as observed in cells. Furthermore, we find that as the strength of the protrusive forces diminish, the system approaches a stabilization of a periodic pattern of protrusions. This result can provide an explanation for a number of puzzling experimental observations regarding cellular shape dependence on the properties of the extra-cellular matrix.
Author Summary
Cells have highly varied and dynamic shapes, which are determined by internal forces generated by the cytoskeleton. These forces include protrusive forces due to the formation of new internal fibers and forces produced due to attachment of the cell to an external substrate. A long standing challenge is to explain how the myriad components of the cytoskeleton self-organize to form the observed shapes of cells. We present here a theoretical study of the shapes of cells that are driven only by protrusive forces of two types; one is the force due to polymerization of actin filaments which acts as an internal pressure on the membrane, and the second is the force due to adhesion between the membrane and external substrate. The key property is that both forces are localized on the cell membrane by protein complexes that have convex spontaneous curvature. This leads to a positive feedback that destabilizes the uniform cell shape and induces the spontaneous formation of patterns. We compare the resulting patterns to observed cellular shapes and find good agreement, which allows us to explain some of the puzzling dependencies of cell shapes on the properties of the surrounding matrix.
doi:10.1371/journal.pcbi.1001127
PMCID: PMC3088653  PMID: 21573201
5.  Propagating Cell-Membrane Waves Driven by Curved Activators of Actin Polymerization 
PLoS ONE  2011;6(4):e18635.
Cells exhibit propagating membrane waves which involve the actin cytoskeleton. One type of such membranal waves are Circular Dorsal Ruffles (CDR) which are related to endocytosis and receptor internalization. Experimentally, CDRs have been associated with membrane bound activators of actin polymerization of concave shape. We present experimental evidence for the localization of convex membrane proteins in these structures, and their insensitivity to inhibition of myosin II contractility in immortalized mouse embryo fibroblasts cell cultures. These observations lead us to propose a theoretical model which explains the formation of these waves due to the interplay between complexes that contain activators of actin polymerization and membrane-bound curved proteins of both types of curvature (concave and convex). Our model predicts that the activity of both types of curved proteins is essential for sustaining propagating waves, which are abolished when one type of curved activator is removed. Within this model waves are initiated when the level of actin polymerization induced by the curved activators is higher than some threshold value, which allows the cell to control CDR formation. We demonstrate that the model can explain many features of CDRs, and give several testable predictions. This work demonstrates the importance of curved membrane proteins in organizing the actin cytoskeleton and cell shape.
doi:10.1371/journal.pone.0018635
PMCID: PMC3080874  PMID: 21533032

Results 1-5 (5)