Coiled coil 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. 

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... 

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]. 

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. 

The coiled-coil motif is not strictly a specific fold but the description is appHed to structures where helical segments are based on the heptad repeat abcdefg) . 

Coiled-coil a-HeUx abcdefg heptad repeat Hydrophobic packing (a d residues) guided by electrostatics (e g residues) Parallel... 

The staggered pattern, unlike the design in the SAF peptides modulated by the side chain interaction, was created because of the identical heptad repeats along the entire peptide that tends to form offsets within the multistranded coiled coil assembly. The resultant stmcture with overhanging ends presents the hydrophobic amino... 

Figure 14.3 Helical wheel diagram of the YZl peptide and the schematic representation of the staggered dimer formation with an axial displacement of three heptad repeating units, which promote elongation into coiled coil fibrils. Reprinted from Zimenkov et al. (2004). Copyright 2004 Elsevier Science.

Figure 14.6 Structural arrangement of peptides (a and c) 1 (EIAQLEYEISQLEQ) and (b and d) 3 (EIAYIEQEISQLEQ) in the coiled coil or amyloid-fike /8-sheet packing motifs. Amino acids are represented with upper case standard single letter code whereas position in the heptad repeat is indicated in lowercase italic. Reprinted from Dong and Hartgerink (2007). Copyright 2007 American Chemical Society.

The original system is based on peptides that contain heptad repeats, where the first and fourth positions of the repeat are hydrophobic amino acids. Such sequences form a-helices, which assemble into coiled-coil structures, as represented in Figure 7.10. The principle is then the same as that used for von Kiedrowski s self-replicating nucleotides (von Kiedrowski 1986), in the sense that a full-length peptide template (having in this case 32-35 residues) directs the condensation of the two half-length peptide substrates. 

Figure 7.10 Coiled-coil structures during peptide condensation, (a) Two peptides containing heptad repeats (A to F and A to F ) able to form a-helices. Hydrophobic interactions (A-A and D-D ) lead to coiled-coil structures, (b) A full-length peptide (T) acts as a template forming a coiled-coil structure with peptide fragments and directing their condensation in other full-length peptides (B). (Adapted from (a) Paul and Joyce, 2004 (b) Ghosh and Chmielewsld, 2004.)...

Helix bundles. A third peptide chain can be added to a coiled coil to form a triple-stranded bundle.180-183 An example is the glycoprotein laminin found in basement membranes. It consists of three peptide chains which, for -600 residues at their C-terminal ends, form a three-stranded coil with heptad repeats.182184 Numerous proteins are folded into four helical segments that associate as four-helix bundles (Fig. 2-22).185-188 These include electron carriers, hormones, and structural proteins. The four-helix bundle not only is a simple packing arrangement, but also allows interactions between the + and - ends of the macro-dipoles of the helices. 

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