Foot Stepper.jpg

Our ability to walk bipedally requires that each foot alternately pushes off from the ground and swings forward. Similarly, each head of a bi-pedaling motor protein advances by cycling through three states, one in which the head produces force, a second in which it transition to the next binding site, and a third in which it rebinds to its track.

The cyclical transformation between the three states, and the structural changes leading to the force-producing powerstroke, are dependent on tight communication between catalytic and mechanical sites within the head.

The catalytic site is where binding and hydrolysis of ATP take place, and from where small changes in conformation are expanded and structurally amplified into larger mechanical rearrangements that set the head in motion.

The cyclical chain of catalytic and mechanical events is known as the chemomechanical cycle. Described below is the chemomechanical cycle of each brand of motor protein. 

How the two heads of a stepping motor coordinate their chemomechanical cycles to produce movement is illustrated under STEPPING.   



Dynein Mechanochemistry.jpg

1. Following termination of the powerstroke and release of ADP, the nucleotide-free dynein head (D) remains strongly attached to the microtubule.

2. Binding of ATP produces a series of structural changes that restore the head (D·ATP) to its pre-powerstroke state. First, the slender microtubule-binding element adopts a microtubule low-affinity conformation leading to rapid dissociation.

3. Next, the force-amplifying structure assumes its pre-powerstroke position and ATP is hydrolyzed to ADP and Pi (D·ADP·Pi).

4. After hydrolysis, the microtubule-binding element resumes its high-affinity conformation leading to microtubule re-association and release of Pi (D·ADP). The force-amplifying structure delivers the powerstroke and force is produced. Dissociation of ADP allows ATP to rebind and the head to enter a new chemomechanical cycle.



KINESIN-1, -2 AND -3 

Kinesin Mechanochemistry.jpg

In contrast to cytoplasmic dynein and the myosin's, the kinesin's exhibit high filament binding affinity in the ATP and ADP·Pi states. and low affinity in the ADP state. 

1. ADP is released and the nucleotide-free head (K) docks onto the microtubule with high affinity.

2 Binding of ATP (K·ATP) drives a shift in position of the force-amplifying neck-linker, i.e. the powerstroke, and force is produced. 

3. The head remains strongly bound to the microtubule during hydrolysis of ATP to ADP and Pi. 

4. Release of Pi undocks the kinesin head (K·ADP). The now unrestrained head swings forward to the next microtubule binding site and resumes a new chemomechanical cycle. 




Myosin Mechanochemistry.jpg

1. Following termination of the powerstroke and release of ADP, the myosin head (M) remains attached to the actin filament with high affinity.

2. Binding of ATP rapidly releases the head (M·ATP), and the force-amplifying structure resumes its pre-powerstroke position.

3. The head remains dissociated from its track during ATP hydrolysis (M·ADP·Pi).

4. Rebinding to actin and release of Pi (M·ADP) trigger a quick displacement of the "neck" structure. The myosin "neck", which is 8 times longer than kinesin's "neck linker", acts as a torque-generating lever arm that drives the powerstroke.

To prevent premature detachment of the myosin motor following the powerstroke, release of ADP and/or rebinding of ATP is under tight regulatory control  (see STEPPING).