Tropomyosin coiled-coil structure

Figure 19-9 Stereoscopic ribbon drawing of the proposed structure of a thin actin filament with tropomyosin coiled-coils bound on opposing sides.124 Five actin nomomers are assembled in the structure as is also illustrated in Fig. 7-10. From Lorenz et al.125 Courtesy of Michael Lorenz.

By examining the amino add sequence of tropomyosin, the smallest and simplest proteins postulated at the time 1819 to contain the coiled-coil motif, we identified the hydrophobic repeat responsible for the formation and stabilization of the coiled-coil structure. 18 A coiled coil can be considered as a repeating heptad of seven amino acid residues a-b-c-d-e-f-g, where positions a and d are occupied by hydrophobic residues. This 3-4 (or 4-3) hydro-... 

McLachlan, A. D., and Stewart, M. (1975). Tropomyosin coiled-coil interactions Evidence for an unstaggered structure. J. Mol. Biol. 98, 293-304. 

Sodek, J., Hodges, R. S., Smillie, L. B., andjurasek, L. (1972). Amino acid sequence of rabbit skeletal tropomyosin and its coiled-coil structures. Proc. Nat. Acad. Sci. USA 69, 3800-3804. 

Tropomyosin is a muscle protein, and has an unusual amino acid sequence consisting of seven residues, (a-b-c-d-e-f-g) . There is the tendency for hydro-phobic amino acid residues to be located at positions a and d in this sequence, and in many cases, the hydrophilic amino acid residues are in other positions (b, c, e, f and g). It has been suggested that this sequence forms coiled-coil a-helix ropes, which is one of the supersecondary structures of proteins. A schematic picture of the cross-section of the coiled-coil structure is shown in Fig. 23.21. 

Fig. 23.21. A schematic picture of the cross-section of the coiled-coil structure in tropomyosin.

Tropomyosin 3 (TMP3, also known as TRK or NEMl) gene located on chromosome lq25 encoding a 284 amino acid protein with coiled coil structure involved in the calcium-dependent actin-myosin interaction. This gene is the fusion partner of the ALK gene in the t(l 2)(q25 p23) translocation. This translocation seems to be the most common translocation associated with the inflammatory myofibroblastic tumor but it is also detected in other tumors such as the anaplastic large cell lymphoma discussed in a later section. 

A second widely used sequence-based approach relies on matrices of residue frequencies, pioneered by Parry (1982). He showed that the residue distribution at the seven heptad positions of the putative coiled-coil segments of myosin, tropomyosin, o-keratin, and hemaglutinin are asymmetric, and proposed a method by which the residue frequencies could be used to predict whether a sequence of unknown structure would form a coiled coil. This approach was implemented with modifications in... 

Historically, coiled coils were identified with long fibrous molecules, from which their structural properties had been determined. Fiber diffraction studies on proteins of the k-m-e-f class were highly successful, initially on dried specimens but later also on native samples (Cohen and Holmes, 1963). However, these proteins turned out to be very difficult to analyze by high-resolution X-ray crystallography for the same reasons that made them so amenable to fiber diffraction—their tendency to aggregate into fibers rather than crystals and the extreme dimensions of their asymmetric units. It took decades to obtain a working structure for tropomyosin [at 15 A resolution (Phillips et al., 1986) at 9 A (Whitby et al.,... 

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