The switch-2 active site loop, specifically the Y439 residue, is crucial for fine-tuning the translocation speed and maintaining high processivity of myosin-5.
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Preclinical myosin-5 kinetics require validation in cardiac isoforms; leaves open relevance to human muscle function or therapy.
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 Mg 2+ ‐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 Mg 2+ ‐dependent nucleotide exchange.—Nagy, N.T., Sakamoto, T., Takács, B., Gyimesi, M., Hazai, E., Bikádi, Z., Sellers, J.R., Kovács, 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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Nagy et al. (2010) studied this question.
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