How myosin motors power cellular functions – an exciting journey from structure to function

Llinas, P.; Pylypenko, Olena; Isabet, T.; Mukherjea, Monalisa; Sweeney, H. Lee; Houdusse, Anne

doi:10.1111/j.1742-4658.2011.08449.x

Cited by 19 publications

(16 citation statements)

References 61 publications

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“…The freeenergy changes are computed separately for the unbound state and the IS and OS bound states. Increasing the Mg 2 + polarizability by 10 %, from 0.08 to 0.09 3 , has a very small effect and reduces DG bind by only …”

Section: Tuning Force-field Parametersmentioning

confidence: 97%

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Structure and Thermodynamics of Mg:Phosphate Interactions in Water: A Simulation Study

et al. 2014

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The association of Mg(2+) and H2 PO4 (-) in water can give insights into Mg:phosphate interactions in general, which are very widespread, but for which experimental data is surprisingly sparse. It is studied through molecular dynamics simulations (>100 ns) by using the polarizable AMOEBA force field, and the association free energy is computed for the first time. Explicit consideration of outer-sphere and two types of inner-sphere association provides considerable insight into the dynamics and thermodynamics of ion pairing. After careful assessment of the computational approximations, the agreement with experimental values indicates that the methodology can be extended to other inorganic and biological Mg:phosphate interactions in solution.

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Section: Tuning Force-field Parametersmentioning

confidence: 97%

“…Many proteins perform energy or information transfer with the help of the nucleotide ligands ATP and ADP, or GTP and GDP. [2,3] Many of these phosphates must interact with magnesium. Mg 2 + has an approximately 50 mm concentration in vivo and has been associated with major physiological processes, including cancer and aging.…”

Section: Introductionmentioning

confidence: 99%

Structure and Thermodynamics of Mg:Phosphate Interactions in Water: A Simulation Study

et al. 2014

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“…Following hydrolysis, it is clear that P i must exit the nucleotide-binding pocket by a path that differs from that of ATP entry, as Mg 2+ ?ADP, switch I and switch II completely cover the P i in both kinesin and myosin. It has been suggested that P i release in myosin occurs through a 'back door' opening at the back of the active site, which is observed in a number of myosin structures (Yount et al, 1995;Sweeney and Houdusse, 2010;Llinas et al, 2012). However, this opening is not observed in the rigor-like myosin structures.…”

Section: Frontmentioning

confidence: 80%

“…Following ATP hydrolysis, switch I undergoes movements that disrupt the P i tube and open the active site, providing a pathway for release of P i (bottom). This pathway differs from the 'back door' opening in the active site that has been proposed to provide an exit route for P i release (Yount et al, 1995;Sweeney and Houdusse, 2010;Llinas et al, 2012), but is now considered unlikely (Lawson et al, 2004;Kaliman et al, 2009). Formation of a P i tube by switch I appears to facilitate ATP hydrolysis and also helps explain the essential role of switch I in the catalytic cycle.…”

Section: Frontmentioning

confidence: 99%

Force generation by kinesin and myosin cytoskeletal motor proteins

Kull

Endow

2012

Journal of Cell Science

102

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SummaryKinesins and myosins hydrolyze ATP, producing force that drives spindle assembly, vesicle transport and muscle contraction. How do motors do this? Here we discuss mechanisms of motor force transduction, based on their mechanochemical cycles and conformational changes observed in crystal structures. Distortion or twisting of the central b-sheet -proposed to trigger actininduced P i and ADP release by myosin, and microtubule-induced ADP release by kinesins -is shown in a movie depicting the transition between myosin ATP-like and nucleotide-free states. Structural changes in the switch I region form a tube that governs ATP hydrolysis and P i release by the motors, explaining the essential role of switch I in hydrolysis. Comparison of the motor power strokes reveals that each stroke begins with the force-amplifying structure oriented opposite to the direction of rotation or swing. Motors undergo changes in their mechanochemical cycles in response to small-molecule inhibitors, several of which bind to kinesins by induced fit, trapping the motors in a state that resembles a force-producing conformation. An unusual motor activator specifically increases mechanical output by cardiac myosin, potentially providing valuable information about its mechanism of function. Further study is essential to understand motor mechanochemical coupling and energy transduction, and could lead to new therapies to treat human disease. IntroductionCytoskeletal motors have been intensively studied over the past 25 years, but our understanding of how force is produced by the motors is still incomplete. The first crystal structure of a kinesin motor domain revealed an unexpected structural homology between the kinesins and myosins -the motor domain of both proteins is formed by the same core structural elements, organized in the same way to form the nucleotide-or filament-binding site on opposite sides of the motor domain. These structural elements and their organization are conserved within the kinesin and myosin superfamilies, implying a common mechanism of force generation by the motors. By contrast, the dyneins deviate in overall structure from the kinesins and myosins, and presumably also in their mechanism of energy transduction (Carter et al., 2011;Kon et al., 2011;Kon et al., 2012;Höök and Vallee, 2012;Schmidt et al., 2012). The focus of this Commentary is on the kinesins and myosins, for which more is known regarding the motor force-producing mechanism than for the dyneins. We discuss the mechanochemical cycles of the motors and the conformational changes they undergo, based on crystal structures of the motors in different nucleotide states. We propose possible force-producing mechanisms of the motors and compare their working strokes. We also discuss smallmolecule inhibitors of the kinesins and an activator of myosin, whose analysis has resulted in further insights into motor function. Further information on kinesin inhibitors can be found in a recent review (Good et al., 2011).

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“…5C). This myosin also did not perform in the TIRF assay, either because the concentration needed to dimerize the myosin VI using cargo was prohibitively high for detection using TIRF or because of the well-documented decrease in affinity between myosins and actin in high-salt conditions (45,46).…”

Section: Lovdab Controls Myosin VI Recruitment With High Spatial and mentioning

confidence: 99%

Investigations of human myosin VI targeting using optogenetically controlled cargo loading

French

Sosnick

Rock

2017

Proc. Natl. Acad. Sci. U.S.A.

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Myosins play countless critical roles in the cell, each requiring it to be activated at a specific location and time. To control myosin VI with this specificity, we created an optogenetic tool for activating myosin VI by fusing the light-sensitive Avena sativa phototropin1 LOV2 domain to a peptide from Dab2 (LOVDab), a myosin VI cargo protein. Our approach harnesses the native targeting and activation mechanism of myosin VI, allowing direct inferences on myosin VI function. LOVDab robustly recruits human full-length myosin VI to various organelles in vivo and hinders peroxisome motion in a lightcontrollable manner. LOVDab also activates myosin VI in an in vitro gliding filament assay. Our data suggest that protein and lipid cargoes cooperate to activate myosin VI, allowing myosin VI to integrate Ca 2+, lipid, and protein cargo signals in the cell to deploy in a site-specific manner.otor proteins play countless roles in biology, each requiring the motor to be recruited and activated at a particular time and place inside the cell. To dissect these multiple roles, we must develop tools that allow us to control the recruitment and activation process. One promising technique for achieving this goal is through optogenetics (1). Optogenetics involves the engineering and application of optically controlled, genetically encoded proteins and is transforming the fields of neuro-and cell biology (2, 3). A major benefit of optogenetics is that proteins are activated using light, which allows for high temporal and spatial control over a protein of interest.Myosin VI is a motor protein whose study could particularly benefit from optogenetic control. It is the only myosin known to walk toward the pointed end of actin filaments (4, 5). This property enables it to perform a diverse array of cellular functions, including cell division, endosome trafficking, autophagy, and Golgi and plasma membrane anchoring (6-9). Myosin VI is also autoinhibited, a property that is commonly found in other myosins (10). When myosin VI binds to cargo through specialized adaptor proteins, this autoinhibition is relieved through a poorly understood mechanism likely involving the disruption of an interaction between its cargo binding domain (CBD) and the myosin head (11,12). Dissociation of the CBD from the head both frees the head to bind tightly to actin and exposes dimerization sites throughout the tail domain of myosin VI, allowing it to become a processive dimer (13-15). In some cases, myosin VI could conceivably function as a monomer, for example when fulfilling its role as a membrane tether during spermatid individualization (16). If this is the case, more work is needed to elucidate the cellular signals that determine its oligomeric state at each site of action.Myosin VI has two classes of cargo proteins that bind to distinct, conserved motifs on the myosin VI C terminus (17). Disabled2, or Dab2, belongs to the class of cargo proteins that bind to a conserved WWY site on myosin (18). Optineurin (OPTN) is a member of the second class that binds ...

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How myosin motors power cellular functions – an exciting journey from structure to function

Cited by 19 publications

References 61 publications

Structure and Thermodynamics of Mg:Phosphate Interactions in Water: A Simulation Study

Structure and Thermodynamics of Mg:Phosphate Interactions in Water: A Simulation Study

Force generation by kinesin and myosin cytoskeletal motor proteins

Investigations of human myosin VI targeting using optogenetically controlled cargo loading

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