BIOC3390 Tutorials: 16 & 18 November 1999

Myosin in extra-ocular muscles

These muscles swivel the eyeball, and are among the fastest and most precisely controlled muscles in the human body. They are derived in the embryo from the first three (pre-otic) somites and are consequently innervated by the third, fourth and sixth cranial nerves. The motor units are unusually small, in keeping with their precise control. They are largely composed of fatigue-resistant type 2A fibres, and express a special MYH13 isoform. This may explain why they are spared by some muscle diseases. We are not aware of any kinetic studies on myosin 13 so you should preferably use the kinetic properties of fast muscle myosin for your calculations. See also the paper by Rome et al (1999) [below] on the special considerations that apply to cross-bridge cycling at high shortening speeds.

How much does a human eyeball weigh? The moment of inertia "I" for a solid sphere is 0.4mR2 and these muscles can accelerate this body, rotate it through about 30 degrees, and stop it again in a fraction of a second. What force is necessary for this, how much does each muscle shorten, what is its cross-sectional area, and what is the load and rate of working for the individual thick filaments, when fully activated? Approximate "guestimates" are sufficient for these calculations. The equations of motion for rotation are analogous to those for linear movements:

work done by muscle = force * muscle shortening = eyeball kinetic energy at top speed

kinetic energy = 0.5 * I * w2 where w is in radians/second

Is there a lot of spare capacity in this system, or is each myosin head group likely to be giving its all?

There are numerous myosin isoenzymes, each one exquisitely adapted to its particular physiological role. These proteins differ in their heavy chains and in both types of light chain component. Vertebrates express at least eight distinct heavy chain classes, of which the classic skeletal muscle variants are sub-forms of myosin II. The chromosomal order of these genes is conserved in the human and mouse genomes and may be important for their regulation. Other known heavy chain variants are tabulated below:

 
typegenesfunctionsomim
IMYO1A
MYO1C
MYO1D

many tissues; hearing transduction?
*601478
*601479
*601480
IIMYH1
MYH2
MYH3
MYH4
MYH6
MYH7
MYH8
MYH9
MYH10
MYH11
MYH13
adult fast skeletal muscle
adult skeletal muscle
embryonic skeletal muscle
fetal skeletal muscle
cardiac muscle alpha (atrium)
cardiac muscle beta (ventricle, also type 1 skeletal)
perinatal skeletal muscle
non-muscle: fibroblasts, endothelium, macrophages
non-muscle cells
smooth muscle
extra-ocular muscles
*160730
*160740
*160720
*160742
*160710
*160760
*160741
*160775
*160776
*160745
*603487
VMYO5Amelanosomes, centrosomes, processive motor *160777
VIMYO6hearing, this motor moves backwards *600970
VIIMYO7Ahearing, vision, melanosome transport *276903
IXMYO9B myeloid cells *602129
XMYO10not known*601481
XVMYO15hearing*602666


The motor domain is a relatively constant feature of the numerous myosin variants, but the remainder of these molecules shows enormous variation, in keeping with their differing physiological functions. The following figure derives from the Cambridge MRC muscle website, which specialises in clustal analysis of the myosin genes.


Non-muscle myosins are required for cytokinesis at the end of cell division, when a contractile ring near the plasmalemma divides the cytoplasm of the daughter cells. They are involved in cytoplasmic streaming movements in many tissues, and especially in actively motile cells such as fibroblasts and macrophages. Special myosin variants are required for sensory processes involved in hearing and vision.

The unexpected roles of myosin in hearing and vision have attracted considerable medical interest. It seems likely that myosins are involved in the correct assembly of melanosomes within the pigmented layer of the retina, and also in the correct differentiation of hair cells within the inner ear. These cells display actin-based stereocilia which transduce sound waves and the movement of fluid in the semicircular canals into nerve impulses. In addition to the roles of myosin isoforms in differentiation, myosin has a further function in the adaptation of the hearing transducer to cope with loud and faint noises. The adaptation motor is thought to be myosin 1 beta, which slides an actin-based "needle valve" to almost block an ion channel in the hair cell membrane. Sound vibrations displace the membrane, allowing ions to enter the cell, and this is thought to initiate the signalling process.

Baker, JE et al (1998) A large and distinct rotation of the myosin light chain domain occurs upon muscle contraction. Proc. Natl. Acad. Sci. USA 95(6), 2944-2949. [Click HERE for HTML format, or HERE for the PDF version.]

Borovikov, YS (1999) Conformational changes of contractile proteins and their role in muscle contraction. International Review of Cytology 189, 267-301. [No electronic copies are available.]

Cooke, R (1998) New angle on myosin. Proc. Natl. Acad. Sci. USA 95(6), 2720-2722. [Click HERE for HTML format, or HERE for the PDF version.]

Corrie, JET et al (1999) Dynamic measurement of myosin light-chain-domain tilt and twist in muscle contraction. Nature 400(6743), 425-430. [Write down the volume and page numbers for future reference. Click HERE for access instructions. Click HERE to gain access via the Leeds University network.]

Dobbie, I et al (1998) Elastic bending and active tilting of myosin heads during muscle contraction. Nature 396(6709), 383-387. [Write down the volume and page numbers for future reference. Click HERE for access instructions. Click HERE to gain access via the Leeds University network.]

Dominguez, R et al (1998) Crystal structure of a vertebrate smooth muscle myosin motor domain and its complex with the essential light chain: Visualization of the pre-power stroke state. Cell 94(5), 559-571. [No electronic copies are available.]

Duke, TAJ Molecular model of muscle contraction. (1999) Proc. Natl. Acad. Sci. USA 96(6), 2770-2775. [Click HERE for HTML format, or HERE for the PDF version.]

Garcia et al (1998) Localization of myosin-1 beta near both ends of tip links in frog saccular hair cells. J. Neuroscience 18(21), 8637-8647. [No electronic copies are available.]

Geeves, MA & Holmes, KC (1999) Structural mechanism of muscle contraction. Annual Rev. Biochem. 68, 687-728. [This is a first-class review. Be sure to read it! Click HERE for HTML format, or HERE for the PDF version.]

Goldman, YE (1998) Wag the tail: Structural dynamics of actomyosin. Cell 93(1), 1-4. [No electronic copies are available.]

Holmes, KC (1997) The swinging lever-arm hypothesis of muscle contraction. Current Biology 7(2) R112-R118. [No electronic copies are available.]

Houdusse, A et al (1999) Atomic structure of scallop myosin subfragment S1 complexed with MgADP: A novel conformation of the myosin head. Cell 97(4), 459-470. [No electronic copies are available.]

Irving, M & Goldman, YE (1999) Motor proteins - Another step ahead for myosin. Nature 398(6727), 463-464. [Write down the volume and page numbers for future reference. Click HERE for access instructions. Click HERE to gain access via the Leeds University network.]

Ishijima, A et al (1998) Simultaneous observation of individual ATPase and mechanical events by a single myosin molecule during interaction with actin. Cell 92(2), 161-171. [No electronic copies are available.]

Kitamura, K et al (1999) A single myosin head moves along an actin filament with regular steps of 5.3 nanometres. Nature 397(6715), 129-134. [Write down the volume and page numbers for future reference. Click HERE for access instructions. Click HERE to gain access via the Leeds University network.]

Lumpkin, EA & Hudspeth, AJ (1998) Regulation of free Ca2+ concentration in hair-cell stereocilia. J. Neuroscience 18(16), 6300-6318. [No electronic copies are available.]

Mehta, AD et al (1997) Detection of single-molecule interactions using correlated thermal diffusion. Proc. Nat. Acad. Sci. USA 94, 7927 - 7931. [Click HERE for HTML format, or HERE for the PDF version.]

Mehta, AD et al (1999) Myosin-V is a processive actin-based motor. Nature 400(6744), 590-593. [Write down the volume and page numbers for future reference. Click HERE for access instructions. Click HERE to gain access via the Leeds University network.]

Molloy, JE et al (1995) Single-molecule mechanics of heavy-meromyosin and s1 interacting with rabbit or drosophila actins using optical tweezers. Biophysical Journal 68, 298s-305s. [No electronic copies are available.]

Nishizaka, T et al (1995) Unbinding force of a single motor molecule of muscle measured using optical tweezers. Nature 377, 251-254. [No electronic copies are available.]

Onishi, H et al (1998) Functional transitions in myosin: Formation of a critical salt- bridge and transmission of effect to the sensitive tryptophan. Proc. Natl. Acad. Sci. USA 95(12), 6653-6658. [Click HERE for HTML format, or HERE for the PDF version.]

Rayment, I (1996) The structural basis of the myosin ATPase activity. J. Biol. Chem. 271(27), 15850-15853. [Click HERE for HTML format, or HERE for the PDF version.]

Rayment, I et al (1996) The active site of myosin. Ann. Rev. Physiol. 58, 671-702. [No electronic copies are available.]

Rome, LC et al (1999) Trading force for speed: Why superfast crossbridge kinetics leads to superlow forces. Proc. Natl. Acad. Sci. USA 96(10), 5826-5831. [Click HERE for HTML format, or HERE for the PDF version.]

Ruppel, KM & Spudich, JA (1996) Structure-function analysis of the motor domain of myosin. Ann. Rev. of Cell & Dev. Biol. 12, 543-573. [Click HERE for HTML format, or HERE for the PDF version.]

Sugi, H et al (1998) Evidence for the load-dependent mechanical efficiency of individual myosin heads in skeletal muscle fibers activated by laser flash photolysis of caged calcium in the presence of a limited amount of ATP. Proc. Natl. Acad. Sci. USA 95(5), 2273-2278. [Click HERE for HTML format, or HERE for the PDF version.]

Suzuki, Y et al (1998) Swing of the lever arm of a myosin motor at the isomerization and phosphate-release steps. Nature 396(6709), 380-383. [Write down the volume and page numbers for future reference. Click HERE for access instructions. Click HERE to gain access via the Leeds University network.]

Tsuda, Y et al (1996) Torsional rigidity of single actin filaments and actin-actin bond breaking force under torsion measured directly by in vitro micromanipulation. Proc. Natl. Acad. Sci. USA 93, 12937-12942. [Click HERE for HTML format, or HERE for the PDF version.]

Tyska, MJ et al (1999) Two heads of myosin are better than one for generating force and motion. Proc. Natl. Acad. Sci. USA 96(8), 4402-4407. [Click HERE for HTML format, or HERE for the PDF version.]

Veigel, C et al (1998) The stiffness of rabbit skeletal actomyosin cross-bridges determined with an optical tweezers transducer. Biophysical Journal 75, 1424-1438. [Click HERE for the abstract, or HERE for the full-text PDF version.]

Veigel, C et al (1999) The motor protein myosin-I produces its working stroke in two steps. Nature 398(6727), 530-533. [Write down the volume and page numbers for future reference. Click HERE for access instructions. Click HERE to gain access via the Leeds University network.]

Walker, M et al (1999) Observation of transient disorder during myosin subfragment-1 binding to actin by stopped-flow fluorescence and millisecond time resolution electron cryomicroscopy: Evidence that the start of the crossbridge power stroke in muscle has variable geometry. Proc. Natl. Acad. Sci. USA 96(2), 465-470. [Click HERE for HTML format, or HERE for the PDF version.]

Warshaw, DM et al (1998) Myosin conformational states determined by single fluorophore polarization. Proc. Natl. Acad. Sci. USA 95(14), 8034-8039. [Click HERE for HTML format, or HERE for the PDF version.]

Weiss et al (1999) Comparative Sequence Analysis of the Complete Human Sarcomeric Myosin Heavy Chain Family: Implications for Functional Diversity J. Mol. Biol. 290(1), 61-75. [Click HERE for HTML format, or HERE for the PDF version.]

Wells et al (1999) Myosin VI is an actin-based motor that moves backwards Nature 401, 505 - 508. [Write down the volume and page numbers for future reference. Click HERE for access instructions. Click HERE to gain access via the Leeds University network.]

Yengo, CM et al (1998) Smooth muscle myosin mutants containing a single tryptophan reveal molecular interactions at the actin-binding interface. Proc. Natl. Acad. Sci. USA 95(22), 12944-12949. [Click HERE for HTML format, or HERE for the PDF version.]

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