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A seesaw model for intermolecular gating in the kinesin motor protein.

Sindelar CV - Biophys Rev (2011)

Bottom Line: Recent structural observations of kinesin-1, the founding member of the kinesin group of motor proteins, have led to substantial gains in our understanding of this molecular machine.The new structural information revises or replaces key details of earlier models of kinesin's ATPase cycle that were based principally on crystal structures of free kinesin, and demonstrates that high-resolution characterization of the kinesin-microtubule complex is essential for understanding the structural basis of the cycle.I discuss the broader implications of the seesaw mechanism within the cycle of a fully functional kinesin dimer and show how the seesaw can account for two types of "gating" that keep the ATPase cycles of the two heads out of sync during processive movement.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, SHMC-E25, 333 Cedar Street, New Haven, CT 06520-8024 USA.

ABSTRACT
Recent structural observations of kinesin-1, the founding member of the kinesin group of motor proteins, have led to substantial gains in our understanding of this molecular machine. Kinesin-1, similar to many kinesin family members, assembles to form homodimers that use alternating ATPase cycles of the catalytic motor domains, or "heads", to proceed unidirectionally along its partner filament (the microtubule) via a hand-over-hand mechanism. Cryo-electron microscopy has now revealed 8-Å resolution, 3D reconstructions of kinesin-1•microtubule complexes for all three of this motor's principal nucleotide-state intermediates (ADP-bound, no-nucleotide, and ATP analog), the first time filament co-complexes of any cytoskeletal motor have been visualized at this level of detail. These reconstructions comprehensively describe nucleotide-dependent changes in a monomeric head domain at the secondary structure level, and this information has been combined with atomic-resolution crystallography data to synthesize an atomic-level "seesaw" mechanism describing how microtubules activate kinesin's ATP-sensing machinery. The new structural information revises or replaces key details of earlier models of kinesin's ATPase cycle that were based principally on crystal structures of free kinesin, and demonstrates that high-resolution characterization of the kinesin-microtubule complex is essential for understanding the structural basis of the cycle. I discuss the broader implications of the seesaw mechanism within the cycle of a fully functional kinesin dimer and show how the seesaw can account for two types of "gating" that keep the ATPase cycles of the two heads out of sync during processive movement.

No MeSH data available.


Related in: MedlinePlus

Cartoon schematic indicating how forward strain on the neck linker could interact with the seesaw to promote detachment in the absence of ATP. The forward strain would favor docking of the neck linker into the docking pocket, thus promoting leftward tilting of the seesaw. However, if ATP is not bound, collapse of the switch pocket would lead to steric interference with I254 in the switch II helix extension in the leftward-tilted case. This action therefore promotes melting of the extension and accompanying weakening of the kinesin–microtubule interaction
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Fig5: Cartoon schematic indicating how forward strain on the neck linker could interact with the seesaw to promote detachment in the absence of ATP. The forward strain would favor docking of the neck linker into the docking pocket, thus promoting leftward tilting of the seesaw. However, if ATP is not bound, collapse of the switch pocket would lead to steric interference with I254 in the switch II helix extension in the leftward-tilted case. This action therefore promotes melting of the extension and accompanying weakening of the kinesin–microtubule interaction

Mentions: The seesaw model accounts for load-dependent release of the microtubule-attached kinesin•ADP motor domain in the following way (Fig. 5). In the absence of ATP, the switch pocket collapses and prevents the seesaw from tilting leftward without introducing severe steric overlap between the switch loops and I254 from the switch II helix extension (Fig. 5a). Forward strain on the neck linker, however, favors its docked conformation, which in turn requires leftward tilting of the seesaw. The only way to accommodate the resulting steric overlap between I254 and the switch loops is for the helix extension to revert to its loop structure (seen in crystal structures), which would abolish the interaction seen between residue N255 in the extension and the microtubule surface (Sindelar and Downing 2007), thus destabilizing the kinesin–microtubule interaction. Thus, under forward strain the seesaw model suggests a pathway for microtubule detachment of kinesin•ADP that involves melting of the switch II helix extension, thus accounting for a critical regulatory step in kinesin’s ADP-gated behavior (Fig. 5b).Fig. 5


A seesaw model for intermolecular gating in the kinesin motor protein.

Sindelar CV - Biophys Rev (2011)

Cartoon schematic indicating how forward strain on the neck linker could interact with the seesaw to promote detachment in the absence of ATP. The forward strain would favor docking of the neck linker into the docking pocket, thus promoting leftward tilting of the seesaw. However, if ATP is not bound, collapse of the switch pocket would lead to steric interference with I254 in the switch II helix extension in the leftward-tilted case. This action therefore promotes melting of the extension and accompanying weakening of the kinesin–microtubule interaction
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3117274&req=5

Fig5: Cartoon schematic indicating how forward strain on the neck linker could interact with the seesaw to promote detachment in the absence of ATP. The forward strain would favor docking of the neck linker into the docking pocket, thus promoting leftward tilting of the seesaw. However, if ATP is not bound, collapse of the switch pocket would lead to steric interference with I254 in the switch II helix extension in the leftward-tilted case. This action therefore promotes melting of the extension and accompanying weakening of the kinesin–microtubule interaction
Mentions: The seesaw model accounts for load-dependent release of the microtubule-attached kinesin•ADP motor domain in the following way (Fig. 5). In the absence of ATP, the switch pocket collapses and prevents the seesaw from tilting leftward without introducing severe steric overlap between the switch loops and I254 from the switch II helix extension (Fig. 5a). Forward strain on the neck linker, however, favors its docked conformation, which in turn requires leftward tilting of the seesaw. The only way to accommodate the resulting steric overlap between I254 and the switch loops is for the helix extension to revert to its loop structure (seen in crystal structures), which would abolish the interaction seen between residue N255 in the extension and the microtubule surface (Sindelar and Downing 2007), thus destabilizing the kinesin–microtubule interaction. Thus, under forward strain the seesaw model suggests a pathway for microtubule detachment of kinesin•ADP that involves melting of the switch II helix extension, thus accounting for a critical regulatory step in kinesin’s ADP-gated behavior (Fig. 5b).Fig. 5

Bottom Line: Recent structural observations of kinesin-1, the founding member of the kinesin group of motor proteins, have led to substantial gains in our understanding of this molecular machine.The new structural information revises or replaces key details of earlier models of kinesin's ATPase cycle that were based principally on crystal structures of free kinesin, and demonstrates that high-resolution characterization of the kinesin-microtubule complex is essential for understanding the structural basis of the cycle.I discuss the broader implications of the seesaw mechanism within the cycle of a fully functional kinesin dimer and show how the seesaw can account for two types of "gating" that keep the ATPase cycles of the two heads out of sync during processive movement.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, SHMC-E25, 333 Cedar Street, New Haven, CT 06520-8024 USA.

ABSTRACT
Recent structural observations of kinesin-1, the founding member of the kinesin group of motor proteins, have led to substantial gains in our understanding of this molecular machine. Kinesin-1, similar to many kinesin family members, assembles to form homodimers that use alternating ATPase cycles of the catalytic motor domains, or "heads", to proceed unidirectionally along its partner filament (the microtubule) via a hand-over-hand mechanism. Cryo-electron microscopy has now revealed 8-Å resolution, 3D reconstructions of kinesin-1•microtubule complexes for all three of this motor's principal nucleotide-state intermediates (ADP-bound, no-nucleotide, and ATP analog), the first time filament co-complexes of any cytoskeletal motor have been visualized at this level of detail. These reconstructions comprehensively describe nucleotide-dependent changes in a monomeric head domain at the secondary structure level, and this information has been combined with atomic-resolution crystallography data to synthesize an atomic-level "seesaw" mechanism describing how microtubules activate kinesin's ATP-sensing machinery. The new structural information revises or replaces key details of earlier models of kinesin's ATPase cycle that were based principally on crystal structures of free kinesin, and demonstrates that high-resolution characterization of the kinesin-microtubule complex is essential for understanding the structural basis of the cycle. I discuss the broader implications of the seesaw mechanism within the cycle of a fully functional kinesin dimer and show how the seesaw can account for two types of "gating" that keep the ATPase cycles of the two heads out of sync during processive movement.

No MeSH data available.


Related in: MedlinePlus