Dyneins motor domains

Eshel, D. (1995). Functional dissection of the dynein motor domain. Cell Motil. Cytoskeleton 32, 133-135. 

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 characteristic (consensus) sequence ofP-loops (the Walker A motif Walker et al., 1982) is Gly-x-x-x-x-Gly-Lys-Thr/Ser (the region in red in Fig. 5) this sequence is often used in bioinformatic searches to identify proteins related to this family. Each myosin and kinesin has a single P-loop. For example, Dictyostelium myosin II has the sequence as in Fig. 5 (179) G-E-S-G-A-G-K-T (186). On the other hand, dynein, with a heavy chain that partly forms a ringlike core complex of six AAA+ domains, has P-loop motifs in the first four of these domains (e.g., G-P-A-G-P-G-K-T). There may be a complex series of interactions between these various sites to generate movement, but the P-loop in the third domain has been shown to be essential for dynein motor function (Silvanovich et al., 2003). 

Silvanovich, A., Li, M-G., Serr, M., Mische, S., and Hays, T. S. (2003). The third P-loop domain in cytoplasmic dynein heavy chain is essential for dynein motor function and ATP-sensitive microtubule binding. Mol. Biol. Cell 14, 1355-1365. 

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. 

In this section, we first summarize the basic models used [67-69] for the description of kinesin and dynein motions driven by ATP hydrolysis. For both kinesin and dynein, two-dimensional master equations are used to describe the motion of the protein motors, although the variables represented by the two dimensions are different. In the case of kinesin, these two variables are used to describe the positions of the two motor domains and, for dynein, to be able to treat the variable chemomechanical coupling, one variable is used to describe its physical motion along the microtubule and the other used to describe its chemical coordinate. 

Kinesin and myosin make up for an interesting comparison. Kinesin is microtubule-based it binds to and carries cargoes along microtubules whereas myosin is actin-based. The motor domain of kinesin weighs one third the size of that of myosin and one tenth of that of dynein [15]. Before the advent of modern microscopic and analytic techniques, it was beheved that these two have little in common. However, the crystal structures available today indicate that they probably originated from a common ancestor [16]. 

Straube A, Enard W., Berner A., Wedlich-Soldner R., Kahmann R., and Steinberg G. 2001. A split motor domain in a cytoplasmic dynein. EMBO J. 20 5091-5100. 

Comparison of the amino acid sequences of myosins, kinesins, and dyneins did not reveal significant relationships between these protein families but, after their three-dimensional structures were determined, members of the myosin and kinesin families were found to have remarkable similarities. In particular, both myosin and kinesin contain P-loop NTPase cores homologous to those found in G proteins. Sequence analysis of the dynein heavy chain reveals it to be a member of the AAA subfamily of P-loop NTPases that we encountered previously in the context of the 19S proteasome (Section 23.2.21. Dynein has six sequences encoding such P-loop NTPase domains arrayed along its length. Thus, we can draw on our knowledge of G proteins and other P-loop NTPases as we analyze the mechanisms of action of these motor proteins. 

PPIases are also associated with motor proteins the first PPIase domain of hFKBP52 (and to a lesser extent hCyp40) binds to the microtubule-associated motor protein dynein [21] and some authors propose that the amino acyl proline CTI plays an important part in the protein transconformation that directs relative molecular motion in contractile muscle fibers [22]. However, there is presently no evidence that PPIases are directly implicated in muscle diseases. 

FIGURE 3-23 Motor protein-dependent movement of cargo. The head domains of myosin, dynein, and kinesin motor proteins bind to a cytoskeletal fiber (microfilaments or microtubules), and the tail domain attaches to one of various types of cargo—in this case, a membrane-limited vesicle. Hydrolysis of ATP in the head domain causes the head domain to "walk" along the track in one direction by a repeating cycle of conformational changes. 

Michaelis-Menten constants, 50 myosin motors, 65 neck-linker, 49 six AAA domains, dynein, 52 thermal ratchet model, 63 unbinding force, 49 Color tuning, energy flow pathways... 

FIP-2, also called NEMO-related protein, contains two leucine zipper domains. Overexpression of FIP-2 does not cause cell death, but can reverse the protective effect of 14.7K on cell death induced by overexpression of the TNFR intracellular domain or RIP (Li et al. 1998). FIP-1 is identical to RagA and belongs to the family of small GTPases (Li et al. 1997). It does not cause cell death but forms ternary complexes with 14.7K and TCTEL, a component of the microtubule motor protein dynein (Horwitz 2001). It will be interesting to see whether these interactions of 14.7K are also detectable during virus infection and whether they influence the TNF signal cascade. 

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