Sequence repeats, in fibrous proteins

STRUCTURAL AND FUNCTIONAL IMPLICATIONS OF SEQUENCE REPEATS IN FIBROUS PROTEINS... 

Structural and Functional Implications of Sequence Repeats in Fibrous Proteins... 

Based on a series of designed elastic-contractile model proteins. Figure 1.2 exhibits a family of curves whereby stepwise linear increases in oil-like character give rise to supra-linear increases in curve steepness, that is, in positive cooperativity. More oil-like phenylalanine (Phe, F) residues with the side chain -CH2-C6H5 replace less oil-like valine (Val, V) residues with the side chain -CH-(CH3)2. Here the structural symmetry is translational with as many as 42 repeats (Model protein v) of the basic 30-residue sequence, and the structure is designed beginning with a repeating five-residue sequence of a fibrous protein, the mam-mahan elastic fiber. 

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. 

Other fibrous proteins contain extensive regions of pleated sheets. The fibers spun by a silkworm, for example, are made almost entirely of fibroin, a protein composed primarily of just three amino acids glycine (45%), alanine (30%), and serine (12%). Each chain of fibroin contains extensive regions where a sequence of six amino acids occurs repeatedly . .. -Gly-Ser-Gly-Ala-Gly-Ala-. .. Notice that every other amino acid is glycine, which is the smallest amino acid. This alternating arrangement is an important feature in the packing of the strands that make up the pleated sheet. 

Fig. 3. Structure and sequence of repeats present in the fibrous proteins discussed in this chapter. (A) The adenovirus triple -spiral. A single repeat of one of the chains is shown as a stick model colored by atom, the other two as a secondary structure cartoon in yellow and orange. Amino acids contributing to the hydrophobic core are labeled, as is the glycine in the turn. (B) Triple -spiral sequence repeats. Conserved hydrophobic residues are indicated by a hash sign, the conserved glycine or proline by an asterisk. (C) The T4-hber fold. A single repeat of one of the chains is shown as a stick model colored by atom, the other two as a secondary structure cartoon in yellow and orange. Several of the conserved amino acids are labeled. (D) Repeating sequences present in bacteriophage T4 fiber proteins (Cerritelli et al., 1996). Conserved amino acids are indicated by a small letter conserved hydrophobic residues by a hash sign, and conserved small amino acids by a dot.

Fibrous protein sequences are often characterized by the presence of simple repetitive motifs. Some are exact in length and/or sequence, but others are only approximate and display considerable variation. Some motifs contain residues that are absolutely conserved in some positions, whereas in others it is only the sequence character that is maintained over the repeat length. In many fibrous proteins the repeats occur contiguously, whereas in others they are found widely separated in the sequence. The varieties of sequence repeat that have been observed are typed and catalogued here by Parry (Chapter 2). Each motif forms a discrete element of structure in many instances, these are arranged helically with respect to one another. In many cases an elongate structure is formed, and this can lead naturally to molecular aggregation and the formation of functional filaments. 

In order to bring some order to what is clearly a diverse array of observations, this review has attempted to categorize the repeats. Five such classes have been recognized. Each will be dealt with in turn and appropriate examples presented. No attempt has been made to list the repeats observed in the sequences of all proteins instead, representative examples are presented from the fibrous proteins in particular, and the proteins associated with them, in order to illustrate key features of some of the more interesting structures. First, however, these classes are defined. 

Type C repeats are very common in proteins. They are quantal in length, but the repeats themselves do not contain residues that are conserved absolutely in any position. However, several positions within the repeats are strongly conserved in character. A classic example of a Type C repeat is that given by the heptad substructure in a-fibrous proteins. This has the form (a—b-c—d—e—f—g)n with the a and d positions generally occupied by apolar residues, and the e and g positions by charged or hydrophilic residues. The heptad is characteristic of an Q-helical conformation (Cohen and Parry, 1986, 1990 Lupas, 1996), but comparison of any two sequences with a heptad substructure generally reveals only about 15—20% identity. The motif also implies that several Q-helices will aggregate to form a multistranded left-handed coiled-coil rope to shield the apolar stripes on the surface of the Q-helices from the aqueous environment. 

A sequence repeat found in both fibrous and globular proteins is one in which a functional motif occurs, possibly several times in the sequence but often noncontiguously. This Type E repeat is exemplified by the Ca2+ EF hand, which is a length of sequence specifying a pair of a-helices that... 

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