Force generation by kinesin and myosin cytoskeletal motor proteins

Kull, F. Jon; Endow, Sharyn A.

doi:10.1242/jcs.103911

Cited by 92 publications

(114 citation statements)

References 73 publications

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“…The stabilization of the NL in rigor is related to the reestablishment of complete density corresponding to helix α6. The K5 ADP-rigor transition shows no evidence of the large-scale twisting of the central β-sheet that is observed in the evolutionarily related region of myosin (27). This comparison does not exclude smaller changes in the kinesin β-sheet (e.g., ref.…”

Section: Conformational Changes On Adp Release: Adp To Rigor Transitionmentioning

confidence: 88%

Comprehensive structural model of the mechanochemical cycle of a mitotic motor highlights molecular adaptations in the kinesin family

Goulet

Major

Jun

et al. 2014

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

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Kinesins are responsible for a wide variety of microtubule-based, ATP-dependent functions. Their motor domain drives these activities, but the molecular adaptations that specify these diverse and essential cellular activities are poorly understood. It has been assumed that the first identified kinesin-the transport motor kinesin-1-is the mechanistic paradigm for the entire superfamily, but accumulating evidence suggests otherwise. To address the deficits in our understanding of the molecular basis of functional divergence within the kinesin superfamily, we studied kinesin-5s, which are essential mitotic motors whose inhibition blocks cell division. Using cryo-electron microscopy and determination of structure at subnanometer resolution, we have visualized conformations of microtubule-bound human kinesin-5 motor domain at successive steps in its ATPase cycle. After ATP hydrolysis, nucleotide-dependent conformational changes in the active site are allosterically propagated into rotations of the motor domain and uncurling of the drug-binding loop L5. In addition, the mechanical neck-linker element that is crucial for motor stepping undergoes discrete, ordered displacements. We also observed large reorientations of the motor N terminus that indicate its importance for kinesin-5 function through control of neck-linker conformation. A kinesin-5 mutant lacking this N terminus is enzymatically active, and ATP-dependent neck-linker movement and motility are defective, although not ablated. All these aspects of kinesin-5 mechanochemistry are distinct from kinesin-1. Our findings directly demonstrate the regulatory role of the kinesin-5 N terminus in collaboration with the motor's structured neck-linker and highlight the multiple adaptations within kinesin motor domains that tune their mechanochemistries according to distinct functional requirements. molecular motors | macromolecular assemblies | mitosis | cancer N ucleotide triphosphates are the fuel that powers the cell's machinery. Conversion of this fuel into mechanical work, i.e., mechanochemistry, depends on individual machines and the functional context in which they have evolved. Indeed, elucidation of the mechanochemistry of a particular machine provides critical insight into both its functions and modes of regulation. Kinesins are a superfamily of motors that use ATP to undertake microtubule (MT)-based work. Kinesins operate throughout the cell cycle in many contexts and can generate force toward the MT plus or minus end and also depolymerize MTs (1). The kinesin mechanochemical engine-the motor domain (MD)-is highly conserved, and conformational changes in the active site during the motor's ATPase cycle are transmitted to other parts of the MD to generate force (2). Most of our current knowledge about kinesin mechanochemistry comes from studies of the superfamily founding member, the transport motor kinesin-1 (K1) (2). However, accumulating evidence suggests that small modifications within kinesin MDs have profound effects on their cellular function. The molecul...

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Section: Conformational Changes On Adp Release: Adp To Rigor Transitionmentioning

confidence: 88%

Comprehensive structural model of the mechanochemical cycle of a mitotic motor highlights molecular adaptations in the kinesin family

Goulet

Major

Jun

et al. 2014

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

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“…They are able to work in ensembles to generate large forces, such as during muscle contraction, or as single molecules to transport cargo (93) and 9 classes of dynein (94). The "Mechanism of Linear Motors" section below focuses on the myosin mechanism as an example of linear motion, while the reader is referred to excellent reviews for the kinesin (95) and dynein (94) mechanisms.…”

Section: Linear Motors: Myosin Kinesin and Dyneinmentioning

confidence: 99%

“…Variability in the length of the light-chain binding region in different myosin isoforms helped to prove the hypothesis that this region functions as a lever arm (189). In kinesin, the major difference is that the ATP binding step is associated with force generation, while the hydrolysis step occurs with kinesin bound to the microtubule (95). The neck linker or coiled-coil stalk has been demonstrated to be critical for movement.…”

Section: Mechanism Of Linear Motorsmentioning

confidence: 99%

Biological Nanomotors with a Revolution, Linear, or Rotation Motion Mechanism

Guo

Noji

Yengo

et al. 2016

Microbiol Mol Biol Rev

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SUMMARYThe ubiquitous biological nanomotors were classified into two categories in the past: linear and rotation motors. In 2013, a third type of biomotor, revolution without rotation (http://rnanano.osu.edu/movie.html), was discovered and found to be widespread among bacteria, eukaryotic viruses, and double-stranded DNA (dsDNA) bacteriophages. This review focuses on recent findings about various aspects of motors, including chirality, stoichiometry, channel size, entropy, conformational change, and energy usage rate, in a variety of well-studied motors, including FoF1ATPase, helicases, viral dsDNA-packaging motors, bacterial chromosome translocases, myosin, kinesin, and dynein. In particular, dsDNA translocases are used to illustrate how these features relate to the motion mechanism and how nature elegantly evolved a revolution mechanism to avoid coiling and tangling during lengthy dsDNA genome transportation in cell division. Motor chirality and channel size are two factors that distinguish rotation motors from revolution motors. Rotation motors use right-handed channels to drive the right-handed dsDNA, similar to the way a nut drives the bolt with threads in same orientation; revolution motors use left-handed motor channels to revolve the right-handed dsDNA. Rotation motors use small channels (<2 nm in diameter) for the close contact of the channel wall with single-stranded DNA (ssDNA) or the 2-nm dsDNA bolt; revolution motors use larger channels (>3 nm) with room for the bolt to revolve. Binding and hydrolysis of ATP are linked to different conformational entropy changes in the motor that lead to altered affinity for the substrate and allow work to be done, for example, helicase unwinding of DNA or translocase directional movement of DNA.

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“…These include large scale domain movements where domains move relative to each other over a scale of tens of angstroms. Such motions dramatically re-arrange the overall structure of the protein and have been observed in enzymes such as hexokinase (EC 2.7.1.1) (1-3, 32) and molecular motors such as myosin (25).…”

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confidence: 95%

Modulating Mobility: a Paradigm for Protein Engineering?

McAuley

Timson

2016

Appl Biochem Biotechnol

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Additional Information:Question ResponsePlease select a section/category for your manuscript.Biocatalysis for organic synthesis -Novel and significant advances in biocatalysis for organic synthesis, including chemo-, regio-and enantioselective biotransformation, screening and engineering of novel enzymes for biocatalysis, biocatalyst immobilization, and nonaqueous biocatalysis.Abstract: Proteins are highly mobile structures. In addition to gross conformational changes occurring on, for example, ligand binding, they are also subject to constant thermal motion. The mobility of the protein varies through its structure and can be modulated by ligand binding and other events. It is becoming increasingly clear that this mobility plays an important role in key functions of proteins including catalysis, allostery, cooperativity and regulation. Thus, in addition to an optimum structure, proteins most likely also require an optimal dynamic state. Alteration of this dynamic state through protein engineering will affect protein function. A dramatic example of this is seen in some inherited metabolic diseases where alternation of residues distant from the active site affects the mobility of the protein and impairs function. We postulate that using molecular dynamics simulations, experimental data or a combination of the two it should be possible to engineer the mobility of active sites. This may be useful in, for example, increasing the promiscuity of enzymes. Thus, a paradigm for protein engineering is suggested in which the mobility of the active site is rationally modified. This might be combined with more "traditional" approaches such as altering functional groups in the active site. Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation Manuscript #ABAB-D-16-00805 Modulating mobility: a paradigm for protein engineering? Margaret McAuley and David J. TimsonReviewer: Flexibility of protein plays an important role in protein functions such as activity and stability. Up to now, a number of studies strategized for engineering the protein towards desirable properties are published. The manuscript has a great summary of recent studies based on modulating mobility of protein especially in activity aspect. I recommend its publication after addressing the following issue.Response: We thank the reviewer for his/her support and encouraging remarks.There are also many reports about the improvement of stability of protein by modulating the flexibility of protein. Such as, "Park.H.J et al, Computational approach for designing thermostable Candidaantarctica lipase B by molecular dynamics simulation; Zhu, F., et al, Rational substitution of surface acidic residues for enhancing the thermostability of thermolysin; Chen, J et al, Improving stability of nitrile hydratase by bridging the salt-bridges in specific thermal-sensitive regions, and so on". It would be attractive if the authors could incorporate some examples that explain the relationship between activity and stability modulated by flexibility of prote...

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Force generation by kinesin and myosin cytoskeletal motor proteins

Cited by 92 publications

References 73 publications

Comprehensive structural model of the mechanochemical cycle of a mitotic motor highlights molecular adaptations in the kinesin family

Comprehensive structural model of the mechanochemical cycle of a mitotic motor highlights molecular adaptations in the kinesin family

Biological Nanomotors with a Revolution, Linear, or Rotation Motion Mechanism

Modulating Mobility: a Paradigm for Protein Engineering?

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