1,037 research outputs found
Spatial Organization of the Cytoskeleton enhances Cargo Delivery to Specific Target Areas on the Plasma Membrane of Spherical Cells
Intracellular transport is vital for the proper functioning and survival of a
cell. Cargo (proteins, vesicles, organelles, etc.) is transferred from its
place of creation to its target locations via molecular motor assisted
transport along cytoskeletal filaments. The transport efficiency is strongly
affected by the spatial organization of the cytoskeleton, which constitutes an
inhomogeneous, complex network. In cells with a centrosome microtubules grow
radially from the central microtubule organizing center towards the cell
periphery whereas actin filaments form a dense meshwork, the actin cortex,
underneath the cell membrane with a broad range of orientations. The emerging
ballistic motion along filaments is frequently interrupted due to constricting
intersection nodes or cycles of detachment and reattachment processes in the
crowded cytoplasm. In order to investigate the efficiency of search strategies
established by the cell's specific spatial organization of the cytoskeleton we
formulate a random velocity model with intermittent arrest states. With
extensive computer simulations we analyze the dependence of the mean first
passage times for narrow escape problems on the structural characteristics of
the cytoskeleton, the motor properties and the fraction of time spent in each
state. We find that an inhomogeneous architecture with a small width of the
actin cortex constitutes an efficient intracellular search strategy.Comment: 14 pages, 9 figure
Allocating and splitting free energy to maximize molecular machine flux
Biomolecular machines transduce between different forms of energy. These
machines make directed progress and increase their speed by consuming free
energy, typically in the form of nonequilibrium chemical concentrations.
Machine dynamics are often modeled by transitions between a set of discrete
metastable conformational states. In general, the free energy change associated
with each transition can increase the forward rate constant, decrease the
reverse rate constant, or both. In contrast to previous optimizations, we find
that in general flux is neither maximized by devoting all free energy changes
to increasing forward rate constants nor by solely decreasing reverse rate
constants. Instead the optimal free energy splitting depends on the detailed
dynamics. Extending our analysis to machines with vulnerable states (from which
they can break down), in the strong driving corresponding to in vivo cellular
conditions, processivity is maximized by reducing the occupation of the
vulnerable state.Comment: 22 pages, 7 figure
Molecular motors: design, mechanism and control
Biological functions in each animal cell depend on coordinated operations of
a wide variety of molecular motors. Some of the these motors transport cargo to
their respective destinations whereas some others are mobile workshops which
synthesize macromolecules while moving on their tracks. Some other motors are
designed to function as packers and movers. All these motors require input
energy for performing their mechanical works and operate under conditions far
from thermodynamic equilibrium. The typical size of these motors and the forces
they generate are of the order of nano-meters and pico-Newtons, respectively.
They are subjected to random bombardments by the molecules of the surrounding
aqueous medium and, therefore, follow noisy trajectories. Because of their
small inertia, their movements in the viscous intracellular space exhibits
features that are characteristics of hydrodynamics at low Reynold's number. In
this article we discuss how theoretical modeling and computer simulations of
these machines by physicists are providing insight into their mechanisms which
engineers can exploit to design and control artificial nano-motors.Comment: 11 pages, including 8 embedded EPS figures; Invited article, accepted
for Publication in "Computing in Science and Engineering" (AIP & IEEE
Elastic lever arm model for myosin V
We present a mechanochemical model for myosin V, a two-headed processive
motor protein. We derive the properties of a dimer from those of an individual
head, which we model both with a 4-state cycle (detached, attached with ADP.Pi,
attached with ADP and attached without nucleotide) and alternatively with a
5-state cycle (where the power stroke is not tightly coupled to the phosphate
release). In each state the lever arm leaves the head at a different, but
fixed, angle. The lever arm itself is described as an elastic rod. The chemical
cycles of both heads are coordinated exclusively by the mechanical connection
between the two lever arms. The model explains head coordination by showing
that the lead head only binds to actin after the power stroke in the trail head
and that it only undergoes its power stroke after the trail head unbinds from
actin. Both models (4- and 5-state) reproduce the observed hand-over-hand
motion and fit the measured force-velocity relations. The main difference
between the two models concerns the load dependence of the run length, which is
much weaker in the 5-state model. We show how systematic processivity
measurement under varying conditions could be used to distinguish between both
models and to determine the kinetic parameters.Comment: 15 pages, 15 figures, to appear in Biophys.
Prime movers : mechanochemistry of mitotic kinesins
Mitotic spindles are self-organizing protein machines that harness teams of multiple force generators to drive chromosome segregation. Kinesins are key members of these force-generating teams. Different kinesins walk directionally along dynamic microtubules, anchor, crosslink, align and sort microtubules into polarized bundles, and influence microtubule dynamics by interacting with microtubule tips. The mechanochemical mechanisms of these kinesins are specialized to enable each type to make a specific contribution to spindle self-organization and chromosome segregation
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Altered chemomechanical coupling causes impaired motility of the kinesin-4 motors KIF27 and KIF7.
Kinesin-4 motors play important roles in cell division, microtubule organization, and signaling. Understanding how motors perform their functions requires an understanding of their mechanochemical and motility properties. We demonstrate that KIF27 can influence microtubule dynamics, suggesting a conserved function in microtubule organization across the kinesin-4 family. However, kinesin-4 motors display dramatically different motility characteristics: KIF4 and KIF21 motors are fast and processive, KIF7 and its Drosophila melanogaster homologue Costal2 (Cos2) are immotile, and KIF27 is slow and processive. Neither KIF7 nor KIF27 can cooperate for fast processive transport when working in teams. The mechanistic basis of immotile KIF7 behavior arises from an inability to release adenosine diphosphate in response to microtubule binding, whereas slow processive KIF27 behavior arises from a slow adenosine triphosphatase rate and a high affinity for both adenosine triphosphate and microtubules. We suggest that evolutionarily selected sequence differences enable immotile KIF7 and Cos2 motors to function not as transporters but as microtubule-based tethers of signaling complexes
Motor Property of Mammalian Myosin 10: A Dissertation
Myosin 10 is a vertebrate specific actin-based motor protein that is expressed in a variety of cell types. Cell biological evidences suggest that myosin 10 plays a role in cargo transport and filopodia extension. In order to fully appreciate these physiological processes, it is crucial to understand the motor property of myosin 10. However, little is known about its mechanoenzymatic characteristics. In vitro biochemical characterization of myosin 10 has been hindered by the low expression level of the protein in most tissues. In this study, we succeeded in obtaining sufficient amount of recombinant mammalian myosin 10 using the baculovirus expression system. The movement directionality of the heterologously expressed myosin 10 was determined to be plus end-directed by the in vitro motility assay with polarity-marked actin filament we developed. The result is consistent with the proposed physiological function of myosin 10 as a plus end-directed transporter inside filopodia. The duty ratio of myosin 10 was determined to be 0.6~0.7 by the enzyme kinetic analysis, suggesting that myosin 10 is a processive motor. Unexpectedly, we were unable to confirm the processive movement of dimeric myosin 10 along actin filaments in a single molecule study. The result does not support the proposed function of myosin 10 as a transporter. One possible explanation for this discrepancy is that the apparent nonprocessive nature of myosin 10 is important for generating sufficient force required for the intrafilopodial transport by working in concert with numbers of other myosin 10 molecules while not interfering with each other.
Altogether, the present study provided qualitative and quantitative biochemical evidences for the better understanding of the motor property of myosin 10 and of the biological processes in which it is involved.
Finally, a general molecular mechanism of myosin motors behind the movement directionality and the processivity is discussed based on our results together with the currently available experimental evidences. The validity of the widely accepted ‘leverarm hypothesis’ is reexamined
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