Kinesin motors

Hirose, K, Lockhart, A., Cross, R., and Amos, L., 1995. Nncleodde-depen-dent angnlar change in kinesin motor domain bound to tnbnlin. Nature 376 277-279. 

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. 

Utilization of a similar [Sc(OTf)3-promoted)] approach by Overman on the ger-anylgeraniol-derived cyclization substrate 98 provided the desired tetracyclization product 99, in which the terminator of the cationic cyclization is an arene group. Compound 99 is then transformed into the kinesin motor protein inhibitor adocia-sulfate 1 (Scheme 8.27) [47]. 

Motor proteins move along MTs in an ATP-dependent manner. Members of the superfamily of kinesin motors move only to the plus ends and dynein motors only to the minus ends. The respective motor domains are linked via adaptor proteins to their cargoes. The binding activity of the motors to MTs is regulated by kinases and phosphatases. When motors are immobilized at their cargo-binding area, they can move MTs. 

The membrane tubules and lamellae of the endoplasmic reticulum (ER) are extended in the cell with the use of MTs and actin filaments. Kinesin motors are required for stretching out the ER, whereas depolymerization of microtubules causes the retraction of the ER to the cell centre in an actin-dependent manner. Newly synthesized proteins in the ER are moved by dynein motors along MTs to the Golgi complex (GC), where they are modified and packaged. The resulting vesicles move along the MTs to the cell periphery transported by kinesin motors. MTs determine the shape and the position also of the GC. Their depolymerization causes the fragmentation and dispersal of the GC. Dynein motors are required to rebuild the GC. 

Figure 6. Transport of material along the nerve axon. Materials such as neurotransmitter peptides are synthesized in the cell body and sequestered in vesicles at the Golgi. Vesicles are then transported down the axon towards the synapse by kinesin motors. Other materials are transported from the synapse to the cell body by dynein motors.

Kinesins Motor proteins for microtubule-based synaptic vesicle transport. In Caenorhabditis elegans, akinesin encoded by unc-104 is essential for transport of synaptic vesicles to nerve terminals. 

Mandelkow, E. and Mandelkow, E. M. Kinesin motors and disease. Trends Cell Biol. 12 585-591, 2002. 

KISc Kinesin motor, catalytic domain, ATPase E(MFP) 6(6) 20(20) 2NCD... 

Bogaistfitter, M. Limb g, A. Overman. L.E. Tmnasi, A.L. (1999) Enantioselective total synthesis of the kinesin motor protein inhibitor adociasulfate I. J. Am. Chem. Soc., 121,12206-7. 

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]. 

The movement is processive, kinesin motors typically taking 100 steps before dissociating from the microtubule.201 2123 Kinesin is bound to the microtubule continuously. Its duty ratio is nearly 1.0 (the same is true for the bacterial flagellar motor ... 

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.

From the marine sponge Haliclona sp. (also known as Adocia sp.), a family of hexaprenoid hydroquinones called adociasulfates, have been recently reported as inhibitors of kinesin motors [100,101], These types of compounds were also found in several soft corals, such as Lemnalia africana [102], Okinawan soft coral of Nephthea sp. [103], and the gorgonian Alertogorgia sp., which yielded the cytotoxic tricyclic sesquiterpene, suberosenone [104],... 

The modular design of kinesin motors is nicely illustrated by switching domains between the kinesin arid Ned motors.90 Kinesin moves unidirectionally to one end of microtubules (the plus end), whereas Ned moves in the opposite direction. Replacing the catalytic domain of kinesin with that of Ned gives a motor that still moves in the kinesin direction. Kinesin is highly processive, remaining attached to a single filament (see Chapter 14, section A7), The Ncd-kinesin chimera has the lower processivity of Ned. 

Hirose, K., Fan, J., and Amos, L. A. (1995a). Re-examination of the polarity of microtubules and sheets decorated with kinesin motor domain. J. Mol. Biol. 251, 329-333. 

Microtubules are the intracellular tracks for two classes of motor proteins kinesins and dyneins. During the past few years, the motor domain structures of several kinesins from different organisms have been determined by X-ray crystallography. Compared with kinesins, dyneins are much larger proteins and attempts to crystallize them have failed so far. Structural information about these proteins comes mosdy from electron microscopy. In this chapter, we mainly focus on the crystal structures of kinesin motor domains. 

The first structure of a kinesin motor domain—that of human kinesin-l (formerly named KHC or conventional kinesin )—was determined by Kull and coworkers (1996). This is still the structure of highest resolution (1.8 A PDB code 1BG2) among all structures of conventional kinesins... 

Structural elements that interact with the microtubule surface have been identified by the effect of point mutations (Woehlke et al, 1997) and by fitting crystal structures of kinesin motor domains to low-resolution electron density maps obtained by cryo-electron microscopy of microtubules... 

Structural Alignment of the Switch-1 and Switch-2 Regions of Kinesin Motor Domains with Secondary Structure Assignments and Classification of the Switch-2 Cluster and Neck/Neck Linker Conformations... 

These observations show that there are striking similarities between myosin and kinesin motors, suggesting that both use a similar if not the same mechanism for transforming ATP s free energy into directed motion. There are, however, also notable differences, both in structure and kinetics, which may reflect the diverse functions of the motors. 

Asenjo, A. B., Krohn, N., and Sosa, H. (2003). Configuration of the two kinesin motor domains during ATP hydrolysis. Nat. Struct. Biol. 10, 836-842. 

Kikkawa, M., Okada, Y., and Hirokawa, N. (2000). 15 A resolution model of the monomeric kinesin motor, KIF1A. Cell 100, 241-252. 

Klopfenstein, D. R., Tomishige, M., Stuurman, N., and Vale, R. D. (2002). Role of phosphatidylinositol(4,5)bisphosphate organisation in membrane transport by the Uncl04 kinesin motor. Cell 109, 347-358. 

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