Biomedical Engineering Reference
In-Depth Information
Given the core structural similarities between kinesin and myosin, it was
surprising that there is no obvious lever arm structure in either monomer or
dimer x-ray crystal structures of kinesin. In the structures of the rat kinesin
monomer and dimer [34, 35], the core of the molecule is attached to a coiled-
coil joining the two kinesin heads of the dimer by a 15-a.a.
β
-strand that
is folded along the central
β
-sheet of kinesin, referred to as the neck linker
region. This element is disordered in the original monomer structure solved
by Kull, et al. (see Figure 5.1). Despite the intriguing structural similarities of
kinesin and myosin, kinesin's mechanism could not be determined from x-ray
crystal structure data alone.
Kinesin Mechanism: the Myosin Story Repeats Itself
The same type of observation just described for identifying the structural
states of myosin's lever arm led to the current structural model of kinesin
motility. An ADP-containing x-ray crystal structure with a docked neck linker
[34], which is similar to the darker kinesin molecule in Figure 5.1, was inter-
preted as an ATP-like state. Cryo-electron microscopy as well as electron
paramagnetic resonance (EPR) and fluorescence resonance energy transfer
(FRET) spectroscopy data were consistent with the docked conformation of
the neck linker conformation being predominantly present in the presence of
ATP or ADP
Pi on microtubules [36]. In contrast, kinesin in the nucleotide-
free state, or in the ADP state, showed an undocked conformation. This con-
formation was interpreted as disordered in the monomeric kinesin constructs
used for this study, similar to the original kinesin structure shown in Figure
5.1 [22]. This interpretation led to a model for a conformational change that
directs kinesin toward the plus end of the microtubule. Kinetic experiments
had shown that upon ADP release, the motor binds to microtubules [32].
The transition of the neck linker element from the ADP-like conformation
to the ATP-like conformation, while the motor is bound to microtubules, is
a plus-end directed conformational change. Therefore, although kinesin lacks
the rigid lever arm structure of myosin, motility of both motors is driven by an
ATP-coupled conformational change of the motor on its partner filament. Re-
markably, these conformational changes are propagated from the nucleotide-
and filament-sensing elements to the mechanical elements of both motors in
much the same way. In both motors, the conformational change is transmitted
by an
α
-helix referred to as the “relay helix” , to either myosin's lever arm or
kinesin's neck linker region [1].
·
5.2.3 Dynein
We are now on the verge of understanding the mechanism of dynein motility in
detail, which means we will soon understand the basic mechanisms of all three
classes of eukaryotic cytoskeletal motors. Looking at the structure of dynein,
similarities to the kinesins and myosins seem almost inconceivable. Dynein is a
