Functional adaptation of the switch-2 nucleotide sensor enables rapid processive translocation by myosin-5.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
Nikolett T NagyMihály Kovács

Abstract

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.

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Citations

Feb 22, 2012·Nature Structural & Molecular Biology·Boglárka H VárkutiAndrás Málnási-Csizmadia
Apr 12, 2011·The Journal of Biological Chemistry·Sarah M Heissler, Dietmar J Manstein
Jan 24, 2012·Current Biology : CB·Raymond C MerrittBechara Kachar
Jun 21, 2012·Biophysical Journal·Darshan V TrivediChristopher M Yengo
Jul 10, 2014·The Journal of Biological Chemistry·Anja M SwensonChristopher M Yengo
Jun 9, 2020·Biochimica Et Biophysica Acta. General Subjects·Ana-Nicoleta BondarYuko Okamoto

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