Kinetic Mechanism and Regulation of Myosin VI
Open accessAbstract
Myosin VI is the only pointed end-directed myosin identified and is likely regulated by heavy chain phosphorylation (HCP) at the actin-binding site in vivo. We undertook a detailed kinetic analysis of the actomyosin VI ATPase cycle to determine whether there are unique adaptations to support reverse directionality and to determine the molecular basis of regulation by HCP. ADP release is the rate-limiting step in the cycle. ATP binds slowly and with low affinity. At physiological nucleotide concentrations, myosin VI is strongly bound to actin and populates the nucleotide-free (rigor) and ADP-bound states. Therefore, myosin VI is a high duty ratio motor adapted for maintaining tension and has potential to be processive. A mutant mimicking HCP increases the rate of P(i) release, which lowers the K(ATPase) but does not affect ADP release. These measurements are the first to directly measure the steps regulated by HCP for any myosin. Measurements with double-headed myosin VI demonstrate that the heads are not independent, and the native dimer hydrolyzes multiple ATPs per diffusional encounter with an actin filament. We propose an alternating site model for the stepping and processivity of two-headed high duty ratio myosins.
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Other molecular motors, such as myosins V and VI, are processive.
“Other molecular motors, such as myosins V and VI are also processive (34-36”
From Stepping and Stretching (2003) · cites this paper as [36]
The Kinetic and Structural Implications section states that native double-headed myosin V is processive. For myosin VI, it estimates multiple ATP turnovers per encounter and predicts multiple steps only if each turnover produces a step; the Abstract describes VI as having the potential to be processive, not as established to be processive. Page numbers are not available in our copy. (LLM, conf=0.88)
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Cites
Evidence for alternating head catalysis by kinesin during microtubule-stimulated ATP hydrolysis.
Hackney, D. D. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.15.6865 · Cited by 351 · see citing works
Highly processive microtubule-stimulated ATP hydrolysis by dimeric kinesin head domains
Hackney, D. D. (1995) · Nature · doi:10.1038/377448a0 · Cited by 177 · see citing works
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Research works printed but not linked: 5
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- De La Cruz, E. M., Wells, A. L., Rosenfeld, S. S., Ostap, E. M., and Sweeney, H. L. (1999) Proc. Natl. Acad. Sci. 96, 13726 -13731
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Rosenfeld, S. S., Fordyce, P. M., Jefferson, G. M., King, P. H., & Block, S. M. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300849200 · Cited by 188 · see citing works
Klumpp, L. M., Hoenger, A., & Gilbert, S. P. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0307691101 · Cited by 107 · see citing works
Measuring Kinesin's First Step
Rosenfeld, S. S., Xing, J., Jefferson, G. M., Cheung, H. C., & King, P. H. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m205261200 · Cited by 54 · see citing works
- Authors
- De La Cruz, E. M., Ostap, E. M., & Sweeney, H. L.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Sweeney, H. Lee
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2001-08
- Volume
- 276
- Issue
- 34
- Pages
- 32373-32381
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2155391189
- Cited by
- 234
- References
- 2
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 5 · 2023: 3 · 2022: 6 · 2021: 5 · 2020: 5 · 2019: 4 · 2018: 4 · 2017: 9 · 2016: 8 · 2015: 5 · 2014: 10 · 2013: 8 · 2012: 12
- FWCI
- 11.32
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Yale University
- National Institutes of Health
- National Institute of General Medical Sciences (GM57247)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR-35661, R01AR035661)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- myosin VI, actin-binding site, ADP release, ATP binding, processivity, F-actin
- MeSH terms
- Actins, Adenosine Diphosphate, Adenosine Triphosphatases, Adenosine Triphosphate, Alanine, Animals, Kinetics, Protein Binding, Pyrenes, Spectrometry, Fluorescence, Swine, Threonine, Glutamic Acid, Myosin Heavy Chains, Amino Acid Substitution
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