Heptad repeat

Figure 3.3 Schematic diagram showing the packing of hydrophobic side chains between the two a helices in a coiled-coil structure. Every seventh residue in both a helices is a leucine, labeled "d." Due to the heptad repeat, the d-residues pack against each other along the coiled-coil. Residues labeled "a" are also usually hydrophobic and participate in forming the hydrophobic core along the coiled-coil.

We described in Chapter 3 the basic features of a-helical coiled coils whose amino acid sequences are recognized by heptad repeats a to in which positions a and d frequently are hydrophobic residues (see Figures 3.2 and 3.3). 

The leucine zipper DNA-binding proteins, described in Chapter 10, are examples of globular proteins that use coiled coils to form both homo- and heterodimers. A variety of fibrous proteins also have heptad repeats in their sequences and use coiled coils to form oligomers, mainly dimers and trimers. Among these are myosin, fibrinogen, actin cross-linking proteins such as spectrin and dystrophin as well as the intermediate filament proteins keratin, vimentin, desmin, and neurofilament proteins. 

The coiled-coil fibrous proteins have heptad repeats in their amino acid sequence and form oligomers—usually dimers or trimers—through their coiled coils. These oligomeric units then assemble into fibers. 

Helices widi a heptad repeat of hydrophobic residues... 

Many enveloped viruses share a common mechanism of fusion, mediated by a virus-encoded glycoprotein that contains heptad repeats in its extraceUnlar domain. Dnring the fnsion process, these domains rearrange to form highly structured and thermodynamically stable coiled-coils. Viruses encoding fusion proteins that have these domains inclnde members of the paramyxovirus family (e.g., respiratory syncytial virus, metapneumovirus, and measles virus), ebola virus, influenza, and members of the retroviridae (e.g., human T cell lenkemia virus type-1 and human immunodeficiency virus type-1, HlV-1). Peptide inhibitors of fusion that disrupt the... 

Xu L, Pozniak A, Wildfire A, Stanfield-Oakley SA, Mosier SM, RatcUffe D, Workman J, JoaU A, Myers R, Smit E, Cane PA, Greenberg ML, Pillay D (2005) Emergence and evolution of enfu-virtide resistance following long-term therapy involves heptad repeat 2 mutations within gp4L Antimicrob Agents Chemother 49 1113-1119... 

The characteristic coiled-coil motifs found in proteins share an (abcdefg) heptad repeat of polar and nonpolar amino acid residues (Fig. 1). In this motif, positions a, d, e, and g are responsible for directing the dimer interface, whereas positions b, c, and f are exposed on the surfaces of coiled-coil assemblies. Positions a and d are usually occupied by hydrophobic residues responsible for interhelical hydrophobic interactions. Tailoring positions a, d, e, and g facilitates responsiveness to environmental conditions. Two or more a-helix peptides can self-assemble with one another and exclude hydrophobic regions from the aqueous environment [74]. Seven-helix coiled-coil geometries have also been demonstrated [75]. 

Scholze, P, Freissmuth, M., and Sitte, H. H. (2002) Mutations within an intramembrane leucine heptad repeat disrupt oligomer formation of the rat gaba transporter 1. J. Biol. Chem. 277,43682 13690. 

Figure 1 A helical wheel diagram of a dimeric coiled-coil. Letters a through g denote the seven amino acid residues of a heptad repeating unit. 

Fig. 3. Schematic representation of the organization of hydrophobic residues on the surface of a folded helix based on the heptad repeat, (abcdefg) , where a and d are hydrophobic...

Helical heptad repeat sequences have been reported to be well behaved although they are difficult to characterize by NMR spectroscopy due to spectral overlap. The motifs that have been shown to have native-like properties, and are not highly repetitive, have cores composed of aromatic amino acid side chains of, for example, phenylalanine and tryptophan. In four-helix bundle motifs [1, 2], the /1/la-motif BBAl [5] and the /1-sheet protein Betanova [9], the formation of the folded structure appears to be strongly dependent on such residues although the energetics have not been calculated by substitution studies. As a tentative rule, therefore, the probability of success in the design of a new protein is probably much higher if residues are included that can form aromatic clusters in the core (Fig. 5). 

The conclusions to be drawn so far about what is needed in a design to induce a native-like fold are therefore that the sequences should either show a high degree of symmetry and be based on the heptad repeat [6], or they should have a hydrophobic core that is shape complementary and at least partly aromatic [1,2,5,9]. 

---