Journal
FASEB JOURNAL
Volume 24, Issue 11, Pages 4480-4490Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.10-163998
Keywords
actomyosin; kinetics; nucleotide exchange; single molecule; sliding speed
Categories
Funding
- Fogarty International Center
- National Heart, Lung, and Blood Institute [1 R01-TW007241]
- Hungarian Scientific Research Fund (OTKA) [K71915, NNF78783]
- European Molecular Biology Organization-Howard Hughes Medical Institute
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Active site loops that are conserved across superfamilies of myosins, kinesins, and G proteins play key roles in allosteric coupling of NTP hydrolysis to interaction with track filaments or effector proteins. In this study, we investigated how the class-specific natural variation in the switch-2 active site loop contributes to the motor function of the intracellular transporter myosin-5. We used single-molecule, rapid kinetic and spectroscopic experiments and semiempirical quantum chemical simulations to show that the class-specific switch-2 structure including a tyrosine (Y439) in myosin-5 enables rapid processive translocation along actin filaments by facilitating Mg2(+)-dependent ADP release. Using wild-type control and Y439 point mutant myosin-5 proteins, we demonstrate that the translocation speed precisely correlates with the kinetics of nucleotide exchange. Switch-2 variants can thus be used to fine-tune translocation speed while maintaining high processivity. The class-specific variation of switch-2 in various NTPase superfamilies indicates its general role in the kinetic tuning of Mg2(+)-dependent nucleotide exchange.-Nagy, N.T., Sakamoto, T., Takacs, B., Gyimesi, M., Hazai, E., Bikadi, Z., Sellers, J.R., Kovacs, M. Functional adaptation of the switch-2 nucleotide sensor enables rapid processive translocation by myosin-5. FASEB J. 24, 4480-4490 (2010). www.fasebj.org
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