Kinesin Structures

Fig. 1.7. Dimeric kinesin structure with ADP bound showing the P strands involved in the CNB Pjq is part of NL and Pq is the CS. Prom [24]...

Kikkawa, J., Ishikawa, T, Wakabayashi, T, and Hirokawa, N., 1995. Three-dimensional structure of die kinesin head-microtnbnle complex. Nature 376 274-277. 

Knll, F. J., Sablin, E. P, Lan, R., et al., 1996. Crystal structure of die kinesin motor domain reveals a structural similarity to myosin. Nature 380 550-555. 

Rayment, I., 1996. Kinesin and myosin Molecnlar motors with similar engines. Structure 4 501-504. 

Even though dynein, kinesin, and myosin serve similar ATPase-dependent chemomechanical functions and have structural similarities, they do not appear to be related to each other in molecular terms. Their similarity lies in the overall shape of the molecule, which is composed of a pair of globular heads that bind microtubules and a fan-shaped tail piece (not present in myosin) that is suspected to carry the attachment site for membranous vesicles and other cytoplasmic components transported by MT. The cytoplasmic and axonemal dyneins are similar in structure (Hirokawa et al., 1989 Holzbaur and Vallee, 1994). Current studies on mutant phenotypes are likely to lead to a better understanding of the cellular roles of molecular motor proteins and their mechanisms of action (Endow and Titus, 1992). 

Pfister, K. K., Wagner, M. C., Stenoien, D., Bloom, G. S. and Brady, S. T9. Monoclonal antibodies to kinesin heavy and light chains stain vesicle-like structures, but not microtubules, in cultured cells. /. Cell Biol. 108 1453-1463, 1989. 

With regard to microtubular ultrastructure, micro filaments (5-7 run in diameter) are composed of filamentous actin. The tubule-like structures are formed by a, P-tubulin heterodimers. The wall is composed of 13 parallel protofilaments. Various microtubule-associated proteins and motor proteins (kinesin and dynein) are bound to the wall. The microtubule is a polar structure, i.e., plus and minus ends. 

D. Inhibitors of kinesin activity from structure-based computer screening. Biochemistry. 2000, 39, 2805-2814. 

Adociasulfates 1-6 (380-385) were isolated from a Haliclona (aka Adocia) sp. from Palau and were all inhibitors of kinesin motor proteins [331]. Adociasulfate 2 (381) had earlier been shown to inhibit the activity of the motor protein kinesin by interference with its binding to microtubules [332], An Adocia sp. from the Great Barrier Reef contained adociasulfates 1 (380), 7 (386) and 8 (387), which inhibit vacuolar H -ATPase [333]. Adociasulfates 5 (384) and 9 (388) were obtained from Adocia aculeata from the Great Barrier Reef [334], The structure of adociasulfate 1 (380) was confirmed by an enantioselective total synthesis [335]. Adociasulfate 10 (389) from Haliclona sp. from Palau also inhibits the kinesin motor proteins [336]. 

Microtubules in the long axons of nerve cells function as "rails" for the "fast transport" of proteins and other materials from the cell body down the axons. In fact, microtubules appear to be present throughout the cytoplasm of virtually all eukaryotic cells (Fig. 7-32) and also in spirochetes.311 Motion in microtubular systems depends upon motor proteins such as kinesin, which moves bound materials toward what is known as the "negative" end of the microtubule,312 dyneins which move toward the positive end.310 These motor proteins are driven by the Gibbs energy of hydrolysis of ATP or GTP and in this respect, as well as in some structural details (Chapter 19), resemble the muscle protein myosin. Dynein is present in the arms of the microtubules of cilia (Fig. 1-8) whose motion results from the sliding of the microtubules driven by the action of this protein (Chapter 19). 

Fig. 19-4).212b However, single kinesin heads, which lack the coiled-coil neck region, have a duty ratio of <0.45. The movement is nonpro-cessive.213 The Ned motor is also nonprocessive.214-216 As mentioned previously, the Ned and kinesin motor domains are at opposite ends of the peptide chain, and the motors move in opposite directions along microtubules.217 218 The critical difference between the two motor molecules was found in the neck domains, which gave rise to differing symmetries in the two heads.219 The latter are shown in Fig. 19-20, in which they have been docked onto the tubulin protofilament structure.

Figure 19-20 Model showing the ned and kinesin dimer structures docked onto a tubulin protofilament. The bound ned and kinesin heads are positioned similarly. Because of the distinct architectures of the kinesin and ned necks, the unbound kinesin head points toward the plus end, whereas the unbound ned head is tilted toward the minus end of the protofilament. From Sablin et al.219 Courtesy of Ronald Vale.

Examining these structures and the fact that they are all powered by ATP, the question remains as to how force is actually produced. Geeves and Holmes (2005) argue that myosin acts by the specific coupling between different myosin head states and different positions of the lever arm on the motor domain, so that, once attached to actin, the myosin acts as an ATP-driven motor where the energy released by ATP hydrolysis is direcdy coupled to the performance of mechanical work. However, Marx et al. (2005) argue that in some cases the kinesins appear to act as thermal ratchets. In this case, the attachment of a second head, once the first head has bound, is an event controlled by thermal motion, but, presumably for steric reasons, the head is more likely to bind to the microtubule in the... 

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