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Myosin VI: an innovative motor that challenged the swinging lever arm hypothesis

Nature Reviews Molecular Cell Biology volume 11, pages 128–137 (2010)Cite this article

Subjects

Key Points

  • Myosins are mechanoenzymes that convert the chemical energy derived from ATP hydrolysis into mechanical work.

  • The kinetic cycle of myosin-driven movement consists of four basic steps. First, the myosin catalytic head binds ATP, which releases the head from actin. Second, ATP hydrolysis results in a conformational change of the catalytic head into a pre-stroke state. Third, associated with phosphate release, the head rebinds strongly to actin and undergoes a transition from the pre-stroke state to a post-stroke state. Finally, ADP is released from the catalytic head, allowing ATP to rebind to complete the cycle.

  • The relative movement at the actin–myosin interface is thought to come from the swing of the light chain-binding region during the kinetic cycle. The light chain-binding region therefore acts as a lever arm to amplify small movements in the catalytic head.

  • Myosin VI has challenged this swinging lever arm hypothesis as it moves much larger distances than the initial interpretation of its structure would allow. A combination of single molecule, biophysical and biochemical studies have now examined the unique structural features of myosin VI that allow it to function in accordance with the lever arm theory of myosin motion.

  • The tail domain of myosin VI, which contains a globular three-helix bundle and an unusual stable and relatively rigid single ER/K motif-containing α-helix, explains the ability of myosin VI to take large steps along actin filaments.

  • Myosin VI carries out diverse functions in various cellular processes. An exciting new area in myosin VI research, and for molecular motors in general, is understanding how multiple myosin VI molecules coordinate to function in different cellular processes.

Abstract

The swinging crossbridge hypothesis states that energy from ATP hydrolysis is transduced to mechanical movement of the myosin head while bound to actin. The light chain-binding region of myosin is thought to act as a lever arm that amplifies movements near the catalytic site. This model has been challenged by findings that myosin VI takes larger steps along actin filaments than early interpretations of its structure seem to allow. We now know that myosin VI does indeed operate by an unusual ∼ 180° lever arm swing and achieves its large step size using special structural features in its tail domain.

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Figure 1: The swinging lever arm hypothesis.
Figure 2: Schematic of myosin VI structure and some of its cellular functions.
Figure 3: Schematic of the myosin VI lever arm and tail domains.
Figure 4: Reversing the direction of myosin VI.
Figure 5: Schematic of lever arms in different myosins examined as single-headed species.
Figure 6: The ER/K motif-containing α-helix in the myosin VI lever arm.
Figure 7: Myosin VI as a monomer and a dimer.

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Acknowledgements

J.A.S is supported by grant GM33289 from the National Institutes of Health. S.S. is supported by an American Cancer Society postdoctoral fellowship.

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  1. Department of Biochemistry, B400 Beckman Center, Stanford University School of Medicine, Stanford, 94305-5307, California, USA

    James A. Spudich & Sivaraj Sivaramakrishnan

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Correspondence to James A. Spudich.

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DATABASES

Protein Data Bank

1BR2

2BK1

2MYS

2V26

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Glossary

Stereocilium

A tapered, finger-like projection from hair cells of the inner ear that responds to mechanical displacement with alterations in membrane potential, and thereby mediates sensory transduction.

Coiled coil

A protein structural domain that mediates subunit oligomerization. The most common coiled coil contains two α-helices that twist around each other to form a stable, rod-like structure.

Leucine zipper

A leucine-rich coiled-coil structural motif that is a common dimerization domain found in some proteins involved in regulating gene expression.

Brownian motion

The random, thermally driven motion of small objects in a fluid or gas.

Biased thermal diffusion

The random, thermally driven motion of a small object in a fluid, with a bias introduced by a localized attraction force.

Stroke size

The distance travelled by the end of the lever arm of myosin following a single ATP hydrolysis. For a non-processive myosin, step size and stroke size are used interchangeably. For processive dimeric myosins, step size refers to the distance moved by the centre of mass of the molecule for a single ATP hydrolysis. Thus, for a processive dimer, the step size is the stroke size plus the additional distance the leading head travels by thermal diffusion before binding to actin.

Optical trap

An instrument that uses a focused laser beam to provide an attractive or repulsive force to physically hold and move microscopic dielectric objects.

Fluorescence resonance energy transfer

A process of energy transfer between two fluorophores. It can be used to determine the distance between two attachment positions in a macromolecule or between two molecules.

Small-angle X-ray scattering

(SAXS). A system for nanostructure analysis in which nanosized particles scatter towards small angles. The SAXS pattern provides information on the overall size and shape of these particles.

Circular dichroism

The differential absorption of left- and right-handed circularly polarized light. It is used to determine the secondary structure of proteins.

Persistence length

The length scale over which a structure is rigid.

Tensegrity

Short for tensional integrity. It refers to structures with an integrity that is based on a synergy between balanced tension and compression components.

Molecular dynamic simulations

One of the principal tools in the theoretical study of biological molecules, which calculates the time-dependent behaviour of a molecular system.

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Spudich, J., Sivaramakrishnan, S. Myosin VI: an innovative motor that challenged the swinging lever arm hypothesis. Nat Rev Mol Cell Biol 11, 128–137 (2010). https://doi.org/10.1038/nrm2833

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