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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.


Cartoon schematic indicating how the seesaw mechanism leads to gating between heads of dimeric kinesin. See text for detailed description
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Fig7: Cartoon schematic indicating how the seesaw mechanism leads to gating between heads of dimeric kinesin. See text for detailed description

Mentions: Elements in the preceding discussion may be assembled into a working model describing processive movement by a kinesin dimer, as shown in Fig. 7 which highlights a series of key structural intermediates that may occur in the cycle. In state 1, the trailing head contains bound ATP and/or ADP•Pi within the tightly closed nucleotide-binding cavity of kinesin’s actively hydrolyzing conformation. Neck linker docking in the trailing head biases the partner head to search toward the leading position, where it can attach to the microtubule in an ADP-bound state. In state 2, attachment of the lead head, in concert with rearwards strain on its neck linker, promotes subtle rearrangements in the motor domain (possibly involving L8) that in turn promote the "nucleotide-ejecting" conformation of the switch I loop, causing loss of ADP in this head. Subsequent ATP binding in the lead head, in state 2, is inhibited by rearward strain on the lead head’s neck linker, according to the gating scheme described in Fig. 4. In state 3, catalytic cleavage and phosphate release in the trailing head lead to collapse of the switch pocket, but forward strain on the neck linker of this head prevents compensatory seesaw tilting to relieve the resulting steric overlap between the switch pocket and the I254 from the switch II helix extension. Thus, in state 3, collapse of the switch pocket forces melting of the switch II helix extension, leading to detachment of the trailing head from the microtubule. Subsequently, ATP binding in the leading head resets the system to state 1, but with the kinesin dimer displaced 8 nm towards the microtubule plus end and identity of the leading and trailing heads swapped.Fig. 7


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

Sindelar CV - Biophys Rev (2011)

Cartoon schematic indicating how the seesaw mechanism leads to gating between heads of dimeric kinesin. See text for detailed description
© Copyright Policy
Related In: Results  -  Collection

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

Fig7: Cartoon schematic indicating how the seesaw mechanism leads to gating between heads of dimeric kinesin. See text for detailed description
Mentions: Elements in the preceding discussion may be assembled into a working model describing processive movement by a kinesin dimer, as shown in Fig. 7 which highlights a series of key structural intermediates that may occur in the cycle. In state 1, the trailing head contains bound ATP and/or ADP•Pi within the tightly closed nucleotide-binding cavity of kinesin’s actively hydrolyzing conformation. Neck linker docking in the trailing head biases the partner head to search toward the leading position, where it can attach to the microtubule in an ADP-bound state. In state 2, attachment of the lead head, in concert with rearwards strain on its neck linker, promotes subtle rearrangements in the motor domain (possibly involving L8) that in turn promote the "nucleotide-ejecting" conformation of the switch I loop, causing loss of ADP in this head. Subsequent ATP binding in the lead head, in state 2, is inhibited by rearward strain on the lead head’s neck linker, according to the gating scheme described in Fig. 4. In state 3, catalytic cleavage and phosphate release in the trailing head lead to collapse of the switch pocket, but forward strain on the neck linker of this head prevents compensatory seesaw tilting to relieve the resulting steric overlap between the switch pocket and the I254 from the switch II helix extension. Thus, in state 3, collapse of the switch pocket forces melting of the switch II helix extension, leading to detachment of the trailing head from the microtubule. Subsequently, ATP binding in the leading head resets the system to state 1, but with the kinesin dimer displaced 8 nm towards the microtubule plus end and identity of the leading and trailing heads swapped.Fig. 7

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.