scholarly journals Backstepping mechanism of kinesin-1

2019 ◽  
Author(s):  
Algirdas Toleikis ◽  
Nicholas J. Carter ◽  
Robert A. Cross
Keyword(s):  
Molecular Motors ◽  
Time Window ◽  
Molecular Motor ◽  
High Load ◽  
The State ◽  
Atp Turnover ◽  
Walking Machines ◽  
Weak Binding ◽  
Tightly Coupled ◽  
Mechanochemical Cycle

AbstractKinesin-1 is an ATP-driven molecular motor that transports cellular cargo along microtubules. At low loads, kinesin-1 almost always steps forwards, towards microtubule plus ends, but at higher loads, it can also step backwards. Backsteps are usually 8 nm, but can be larger. These larger backwards events of 16 nm, 24 nm or more are thought to be slips rather than steps, because they are too fast to consist of multiple, tightly-coupled 8 nm steps. Here we propose that not just these larger backsteps, but all kinesin-1 backsteps, are slips. We show firstly that kinesin waits before forward steps for less time than before backsteps and detachments; secondly that kinesin waits for the same amount of time before backsteps and detachments and thirdly that by varying the microtubule type we can change the ratio of backsteps to detachments, without affecting forward stepping. Our findings indicate that backsteps and detachments originate from the same state and that this state arises later in the mechanochemical cycle than the state that gives rise to forward steps. To explain our data, we propose that in each cycle of ATP turnover, forward kinesin steps can only occur before Pi release, whilst backslips and detachments can only occur after Pi release. In the scheme we propose, Pi release gates access to a weak binding K.ADP-K.ADP state that can slip back along the microtubule, re-engage, release ADP and try again to take an ATP-driven forward step. We predict that this rescued detachment pathway is key to maintaining kinesin processivity under load.Significance statementKinesin-1 molecular motors are ATP-driven walking machines that typically step forward, towards microtubule plus ends. But they can also step backwards, especially at high load. Backsteps are currently thought to occur by directional reversal of forwards walking. To the contrary, we propose here that kinesin backsteps are not steps, but slips. We show that backwards translocations originate from a different and later state in the kinesin mechanism than the state that generates forward steps. To explain this, we propose that following ATP binding, kinesin molecules that fail to step forward within a load-dependent time window convert to a state that can slip back, rebind to the microtubule, and try again to step forward.

scholarly journals A model of processive walking and slipping of kinesin-8 molecular motors

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ping Xie
Keyword(s):  
Single Molecule ◽  
Molecular Motors ◽  
External Load ◽  
Molecular Motor ◽  
Velocity Versus ◽  
Stick Slip ◽  
Load Dependence ◽  
Chemomechanical Coupling ◽  
Similarities And Differences ◽  
Stick Slip Motion

AbstractKinesin-8 molecular motor can move with superprocessivity on microtubules towards the plus end by hydrolyzing ATP molecules, depolymerizing microtubules. The available single molecule data for yeast kinesin-8 (Kip3) motor showed that its superprocessive movement is frequently interrupted by brief stick–slip motion. Here, a model is presented for the chemomechanical coupling of the kinesin-8 motor. On the basis of the model, the dynamics of Kip3 motor is studied analytically. The analytical results reproduce quantitatively the available single molecule data on velocity without including the slip and that with including the slip versus external load at saturating ATP as well as slipping velocity versus external load at saturating ADP and no ATP. Predicted results on load dependence of stepping ratio at saturating ATP and load dependence of velocity at non-saturating ATP are provided. Similarities and differences between dynamics of kinesin-8 and that of kinesin-1 are discussed.

Molecular Motors: Force and Movement Generated by Single Myosin II Molecules

Physiology ◽  
2002 ◽  
Vol 17 (5) ◽  
pp. 213-218 ◽  
Author(s):  
Caspar Rüegg ◽  
Claudia Veigel ◽  
Justin E. Molloy ◽  
Stephan Schmitz ◽  
John C. Sparrow ◽  
...  
Keyword(s):  
Optical Tweezers ◽  
Single Molecule ◽  
Molecular Motors ◽  
Molecular Motor ◽  
Myosin Ii ◽  
Force Production ◽  
Myosin Isoforms ◽  
Single Molecule Level ◽  
Recent Developments ◽  
Muscle Myosin

Muscle myosin II is an ATP-driven, actin-based molecular motor. Recent developments in optical tweezers technology have made it possible to study movement and force production on the single-molecule level and to find out how different myosin isoforms may have adapted to their specific physiological roles.

scholarly journals Molecular mechanisms for microtubule length regulation by kinesin-8 and XMAP215 proteins

2014 ◽  
Vol 4 (6) ◽  
pp. 20140031 ◽  
Author(s):  
Louis Reese ◽  
Anna Melbinger ◽  
Erwin Frey
Keyword(s):  
Molecular Motors ◽  
Molecular Mechanisms ◽  
Molecular Motor ◽  
Mutual Exclusion ◽  
High Growth ◽  
Dependent Manner ◽  
Dynamic Regulation ◽  
Filament Dynamics ◽  
Length Regulation ◽  
The Stability

The cytoskeleton is regulated by a plethora of enzymes that influence the stability and dynamics of cytoskeletal filaments. How microtubules (MTs) are controlled is of particular importance for mitosis, during which dynamic MTs are responsible for proper segregation of chromosomes. Molecular motors of the kinesin-8 protein family have been shown to depolymerize MTs in a length-dependent manner, and recent experimental and theoretical evidence suggests a possible role for kinesin-8 in the dynamic regulation of MTs. However, so far the detailed molecular mechanisms of how these molecular motors interact with the growing MT tip remain elusive. Here we show that two distinct scenarios for the interactions of kinesin-8 with the MT tip lead to qualitatively different MT dynamics, including accurate length control as well as intermittent dynamics. We give a comprehensive analysis of the regimes where length regulation is possible and characterize how the stationary length depends on the biochemical rates and the bulk concentrations of the various proteins. For a neutral scenario, where MTs grow irrespective of whether the MT tip is occupied by a molecular motor, length regulation is possible only for a narrow range of biochemical rates, and, in particular, limited to small polymerization rates. By contrast, for an inhibition scenario, where the presence of a motor at the MT tip inhibits MT growth, the regime where length regulation is possible is extremely broad and includes high growth rates. These results also apply to situations where a polymerizing enzyme like XMAP215 and kinesin-8 mutually exclude each other from the MT tip. Moreover, we characterize the differences in the stochastic length dynamics between the two scenarios. While for the neutral scenario length is tightly controlled, length dynamics is intermittent for the inhibition scenario and exhibits extended periods of MT growth and shrinkage. On a broader perspective, the set of models established in this work quite generally suggest that mutual exclusion of molecules at the ends of cytoskeletal filaments is an important factor for filament dynamics and regulation.

scholarly journals Active and Unidirectional Acceleration of Biaryl Rotation by a Molecular Motor

2019 ◽  
Author(s):  
Edgar Uhl ◽  
Peter Mayer ◽  
Henry Dube
Keyword(s):  
Potential Energy ◽  
Motor Unit ◽  
Rate Constants ◽  
Molecular Motors ◽  
Molecular Motor ◽  
Molecular Machine ◽  
Single Bond ◽  
Bond Rotation ◽  
Immense Potential

Light driven molecular motors possess immense potential as central driving units for future nanotechnology. Integration into larger molecular setups and transduction of their mechanical motions represents the current frontier of research. Here we report on an integrated molecular machine setup allowing to transmit potential energy from a motor unit unto a remote receiving entity. The setup consists of a motor unit connected covalently to a distant and sterically strongly encumbered biaryl receiver. By action of the motor unit single bond rotation of the receiver is strongly accelerated and forced to proceed unidirectionally. The transmitted potential energy is directly measured as the extent to which energy degeneration is lifted in the thermal atropisomerization of this biaryl. Energy degeneracy is reduced by as much as 2.3 kcal/mol and rate accelerations up to 2x10<sup>5</sup> fold in terms of rate constants are achieved.<br><b></b>

scholarly journals Positional isomers of a non-nucleoside substrate differentially affect myosin function

2019 ◽  
Author(s):  
M. Woodward ◽  
E. Ostrander ◽  
S.P. Jeong ◽  
X. Liu ◽  
B. Scott ◽  
...  
Keyword(s):  
Energy Source ◽  
Muscle Contraction ◽  
Motor Function ◽  
Molecular Motors ◽  
Molecular Motor ◽  
Vesicular Transport ◽  
Gain Control ◽  
Mechanical Work ◽  
Chemical Energy ◽  
Muscle Myosin

AbstractMolecular motors have evolved to transduce chemical energy from adenosine triphosphate into mechanical work to drive essential cellular processes, from muscle contraction to vesicular transport. Dysfunction of these motors is a root cause of many pathologies necessitating the need for intrinsic control over molecular motor function. Herein, we demonstrate that positional isomerism can be used as a simple and powerful tool to control the molecular motor of muscle, myosin. Using three isomers of a synthetic non-nucleoside triphosphate we demonstrate that myosin’s force and motion generating capacity can be dramatically altered at both the ensemble and single molecule levels. By correlating our experimental results with computation, we show that each isomer exerts intrinsic control by affecting distinct steps in myosin’s mechano-chemical cycle. Our studies demonstrate that subtle variations in the structure of an abiotic energy source can be used to control the force and motility of myosin without altering myosin’s structure.Statement of SignificanceMolecular motors transduce chemical energy from ATP into the mechanical work inside a cell, powering everything from muscle contraction to vesicular transport. While ATP is the preferred source of energy, there is growing interest in developing alternative sources of energy to gain control over molecular motors. We synthesized a series of synthetic compounds to serve as alternative energy sources for muscle myosin. Myosin was able to use this energy source to generate force and velocity. And by using different isomers of this compound we were able to modulate, and even inhibit, the activity of myosin. This suggests that changing the isomer of the substrate could provide a simple, yet powerful, approach to gain control over molecular motor function.

scholarly journals Cilia oscillations

2019 ◽  
Vol 375 (1792) ◽  
pp. 20190157 ◽  
Author(s):  
Yi Man ◽  
Feng Ling ◽  
Eva Kanso
Keyword(s):  
Feedback Control ◽  
Motor Activity ◽  
Molecular Motors ◽  
Molecular Motor ◽  
Control Model ◽  
Eukaryotic Cells ◽  
Sperm Number ◽  
Sliding Motion ◽  
Molecular Machinery ◽  
Oscillation Frequencies

Cilia, or eukaryotic flagella, are microscopic active filaments expressed on the surface of many eukaryotic cells, from single-celled protozoa to mammalian epithelial surfaces. Cilia are characterized by a highly conserved and intricate internal structure in which molecular motors exert forces on microtubule doublets causing cilia oscillations. The spatial and temporal regulations of this molecular machinery are not well understood. Several theories suggest that geometric feedback control from cilium deformations to molecular activity is needed. Here, we implement a recent sliding control model, where the unbinding of molecular motors is dictated by the sliding motion between microtubule doublets. We investigate the waveforms exhibited by the model cilium, as well as the associated molecular motor dynamics, for hinged and clamped boundary conditions. Hinged filaments exhibit base-to-tip oscillations while clamped filaments exhibit both base-to-tip and tip-to-base oscillations. We report the change in oscillation frequencies and amplitudes as a function of motor activity and sperm number, and we discuss the validity of these results in the context of experimental observations of cilia behaviour. This article is part of the Theo Murphy meeting issue ‘Unity and diversity of cilia in locomotion and transport’.

scholarly journals Green light powered molecular state motor enabling eight-shaped unidirectional rotation

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Aaron Gerwien ◽  
Peter Mayer ◽  
Henry Dube
Keyword(s):  
Molecular Motors ◽  
Molecular Level ◽  
Molecular Motor ◽  
Green Light ◽  
Molecular Machines ◽  
Molecular State ◽  
Molecular Devices ◽  
External Energy ◽  
Fixed Sequence ◽  
Crossing Point

Abstract Molecular motors convert external energy into directional motions at the nano-scales. To date unidirectional circular rotations and linear motions have been realized but more complex directional trajectories remain unexplored on the molecular level. In this work we present a molecular motor powered by green light allowing to produce an eight-shaped geometry change during its unidirectional rotation around the central molecular axis. Motor motion proceeds in four different steps, which alternate between light powered double bond isomerizations and thermal hula-twist isomerizations. The result is a fixed sequence of populating four different isomers in a fully unidirectional trajectory possessing one crossing point. This motor system opens up unexplored avenues for the construction and mechanisms of molecular machines and will therefore not only significantly expand the toolbox of responsive molecular devices but also enable very different applications in the field of miniaturized technology than currently possible.

A Dynamic Escape Problem of Molecular Motors

2020 ◽  
Vol 142 (5) ◽  
Author(s):  
Dean Culver ◽  
Bryan Glaz ◽  
Samuel Stanton
Keyword(s):  
Molecular Motors ◽  
Binding Sites ◽  
Molecular Motor ◽  
Myosin Ii ◽  
Three Dimensional ◽  
Production Capacity ◽  
Force Production ◽  
Actin Binding ◽  
Three Dimensional Model ◽  
Thermal Agitation

Abstract Animal skeletal muscle exhibits very interesting behavior at near-stall forces (when the muscle is loaded so strongly that it can barely contract). Near this physical limit, the myosin II proteins may be unable to reach advantageous actin binding sites through simple attractive forces. It has been shown that the advantageous utilization of thermal agitation is a likely source for an increased force-production capacity and reach in myosin-V (a processing motor protein), and here we explore the dynamics of a molecular motor without hand-over-hand motion including Brownian motion to show how local elastic energy well boundaries may be overcome. We revisit a spatially two-dimensional mechanical model to illustrate how thermal agitation can be harvested for useful mechanical work in molecular machinery inspired by this biomechanical phenomenon without rate functions or empirically inspired spatial potential functions. Additionally, the model accommodates variable lattice spacing, and it paves the way for a full three-dimensional model of cross-bridge interactions where myosin II may be azimuthally misaligned with actin binding sites. With potential energy sources based entirely on realizable components, this model lends itself to the design of artificial, molecular-scale motors.

Enhanced Diffusion in a Model of Molecular Motors with Potential Switching

2019 ◽  
Vol 18 (02) ◽  
pp. 1940005 ◽  
Author(s):  
Ryota Shinagawa ◽  
Kazuo Sasaki
Keyword(s):  
Diffusion Coefficient ◽  
External Force ◽  
Molecular Motors ◽  
Periodic Potential ◽  
Brownian Particle ◽  
Molecular Motor ◽  
Free Diffusion ◽  
Enhanced Diffusion ◽  
Additional Peak ◽  
Diffusion Enhancement

Diffusion enhancement is a phenomenon in which the diffusion coefficient of a system is increased by an external force and it becomes larger than that of the force-free diffusion in thermal equilibrium. It is known that this phenomenon occurs for a Brownian particle in a periodic potential under a constant external force. Recently, it was found that diffusion enhancement also occurred in a biological molecular motor, whose moving part could move itself by switching the potentials generated by the other parts. It was shown that the diffusion coefficient exhibited peaks as a function of a constant external force. Here, we report the occurrence of an additional peak and investigate the condition governing its appearance.

Relocation of myosin and actin, kinesin and tubulin in the acrosome reaction of bovine spermatozoa

2009 ◽  
Vol 21 (2) ◽  
pp. 364 ◽  
Author(s):  
Ifigenia Oikonomopoulou ◽  
Hitesh Patel ◽  
Paul F. Watson ◽  
Peter D. Chantler
Keyword(s):  
Molecular Motors ◽  
Acrosome Reaction ◽  
Molecular Motor ◽  
Calcium Ionophore ◽  
Cell Types ◽  
Calcium Ionophore A23187 ◽  
Ionophore A23187 ◽  
Sequence Of Events ◽  
Bovine Spermatozoa ◽  
Number Of Cells

The mammalian acrosome reaction is a specialised exocytotic event. Although molecular motors are known to be involved in exocytosis in many cell types, their potential involvement in the acrosome reaction has remained unknown. Here, it has been shown that actin is localised within the equatorial segment and in the marginal acrosomal ridge of the heads of unreacted bull spermatozoa. Myosins IIA and IIB are found within the anterior acrosomal margins of virtually all sperm cells and, less prominently, within the equatorial segment. Tubulin was detected in the equatorial segment and around the periphery of the acrosome while kinesin was prominent in the equatorial segment. After induction of the acrosome reaction by means of the calcium ionophore A23187, the number of cells exhibiting actin fluorescence intensity in the anterior acrosomal margin decreased four-fold and those displaying equatorial segment fluorescence decreased 3.5-fold; myosin IIA immunofluorescence decreased in intensity with most spermatozoa losing equatorial staining, whereas there was little change in the distribution or intensity of myosin IIB immunofluorescence, except for a ~20% decrease in the number of cells exhibiting acrosomal staining. Tubulin became largely undetectable within the head and kinesin staining spread rostrally over the main acrosome region. A possible sequence of events that ties in these observations of molecular motor involvement with the known participation of SNARE proteins is provided.

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