Saturday, October 2, 2010
I thought a key topic in this chapter was the motion of kinesin. I was confused at first about how this molecule works, but I think I understand now. Please correct me if I am wrong anywhere. Each head of the kinesin molecule has two sites, one which binds one ADP molecule and one which binds to the microtubule. Both these sites bind strongly to their respective substrates. However, the head cannot bind strongly to both substrates at once. This is an example of non-competitive inhibition.
Because these sites bind strongly, and there is an abundance of ADP and microtubule binding sites in the cell compared to kinesin molecules, at least one of these sites is bound at any time. So if the molecule is not bound to the microtubule, then both these heads of the dimer have ADP bound. When the molecule is near a microtubule, eventually one of the heads will lose its ADP and bind to the microtubule. I suppose that a backward step could be taken at this point, and the head bound to the microtubule releases the microtubule and rebinds ADP. However, as the concentration of ATP in the cell is much higher than the concentration of APT, an ATP molecule is more likely to bind to the vacant site on the kinesin head bound to the microtubule.
Unlike ADP, kinesin is able to bind ATP and the microtubule strongly. When the ATP molecule binds, the head does not let go of the microtubule. The neck linker of the bound head then attaches to the head. This state is a local energy minimum. The other head is free to diffuse around; however, the position of the neck linker biases this diffusion. This is the asymmetry which is necessary for directed molecular motion.
Eventually the other head diffuses close enough to the next microtubule binding site for it to bind. However, this head still has ADP bound, so it can only bind weakly to the next site. It is likely that it binds and unbinds several times. However, eventually the head will spontaneously release the ADP, and will be free to bind the microtubule.
The protein chain connecting the two heads is only just long enough to reach the next microtubule binding site, so when both heads are bound, the molecule is strained due to stretching. Since the protein chain is only just long enough to reach the next microtubule binding site, even with the bias in the neck linker, it is nearly impossible for the unbound head to accidentally diffuse close enough to the previous site ad take a step backwards, because the neck linker will always point in the forward direction.
Perhaps this added strain on the molecule deforms the ATP binding site on the initially bound head, which causes it to hydrolyse the ATP bound to it. The head only weakly binds the resulting ADP and the microtubule, so the molecule will likely release one of these substrates. Due to the extra strain the molecule is under in its stretched state, the head preferentially releases the microtubule, to cancel this stress.
The energy released by ATP hydrolysis detaches the neck linker from the head, and the molecule is left with one head bound to the microtubule and one head bound to an ADP molecule. This is the state it began in, thus the cycle is available to repeat, providing the substrate concentrations remain the same. I presume this process will repeat until an ADP binds to the head bound to the microtubule instead of an ATP molecule, and the kinesin molecule detaches from the microtubule altogether.