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#kinesin-1

3 public questions tagged with this topic.

Cytoskeleton

What regulates kinesin-1 activation?

Kinesin-1 regulation avoids gratuitous ATP consumption and traffic jams by autoinhibition mechanism evolutionarily conserved ensuring motor only active when bound to cargo. In cargo free state heavy chain tail IAK motif folds back contacting motor head switch regions blocking microtubule stimulated ADP release maintaining ATPase low about 10 fold inhibition. Light chains also contribute to folded globular conformation compact. Cargo adaptors such as JNK interacting proteins JIP1-3 FEZ1 Milton TRAK bind light chains or tail sterically unfolding molecule to extended active state increasing microtubule affinity 20 fold and ATPase rate. ATP hydrolysis itself occurs in motor domain P loop driving stepping not in stalk domain which serves purely structural coiled coil dimerization role linking heads. Thus activation triggered by cargo binding induced unfolding not stalk ATP hydrolysis. ATP hydrolysis at motor provides energy for movement. This regulatory paradigm ensures motor travels only when loaded linking ATP cycles to cargo availability for processive anterograde movement failure leads to organelle mislocalization neurodegeneration and developmental defects.

Ref: Verhey & Hammond, Nat Rev Mol Cell Biol 2009 – Kinesin-1 activation by cargo binding unfolding mechanism.

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Cytoskeleton

The stalk domain of kinesin-1 is responsible for:

Domain architecture of kinesin-1 reveals clear division of labor essential for processive dimer motor function. N terminal globular motor domain about 340 amino acids contains P loop ATPase site switch I II microtubule binding interface and neck linker for mechanochemistry converting ATP hydrolysis to mechanical step. Immediately C terminal lies neck coiled coil ensuring dimerization of motor domains upon folding critical for hand over hand coordination followed by elongated stalk extending about 50 nm formed by interrupted coiled coil heptad repeats left handed supercoils stabilizing heavy chain dimer through hydrophobic packing of a and d positions leucine zipper like. Disruption of stalk by mutation prevents dimer formation and abolishes processivity yielding monomeric non processive motor. Central hinge regions provide flexibility for autoinhibited folding where C terminal tail interacts with motor domains to block ATPase until cargo binding unfolds. C terminal globular tail binds kinesin light chains via heptad interactions adapting to diverse vesicles mitochondria mRNA. Thus stalk responsible for dimerization via coiled coil interaction not ATP hydrolysis.

Ref: Hirokawa & Noda, Physiol Rev 2008 – Kinesin-1 stalk coiled coil mediated dimerization domain function.

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Cytoskeleton

How does kinesin-1 move along microtubules?

Kinesin-1 conventional motor transports cargo over long distances toward plus ends at velocities up to 1 micron per second. Heavy chain dimerization produces two motor heads coordinated via neck linker docking mechanism. Motility described as processive sliding or walking because motor maintains continuous association via at least one head bound at any moment preventing diffusion away from track essential for long range transport. ATP binding to leading head causes neck linker zipping toward plus end throwing lagging head forward to next binding site 8 nm ahead matching tubulin dimer repeat analogous to hand over hand stepping yet often simplified as sliding motion along filament surface maintaining electrostatic tethering via K loop. Interaction with microtubule via switch regions L8 L12. Tail associates with light chains binding cargo adaptors JIP Milton leading to activation by unfolding autoinhibition relieved only upon cargo binding preventing futile ATP consumption. This continuous attachment ensures efficient organelle movement without loss critical for axonal transport across meter long axons in larger mammals requiring high processivity.

Ref: Vale & Fletterick, Annu Rev Cell Dev Biol – Kinesin-1 sliding walking mechanism along microtubules processivity.

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