A particular combination of two or more secondary structures that form a distinct three-dimensional structure is called a structural motif when it appears in multiple proteins. A structural motif is often, but not always, associated with a specific function. Any particular structural motif will frequently perform a common function in different proteins, such as binding to a particular ion or small molecule—for example, calcium or ATP. Some structural motifs, when isolated from the rest of a protein, are stable, and are thus called structural domains, as we shall see shortly. However other structural motifs do not form thermodynamically stable structures in the absence of other portions of the protein and are thus not considered to be independent structural domains.

One common structural motif is the α helix–based coiled coil, or heptad repeat. Many proteins, including fibrous proteins and DNA-regulating proteins called transcription factors (see Chapter 9), assemble into dimers or trimers by using a coiled-coil motif, in which α helices from two, three, or even four separate polypeptide chains coil about one another—resulting in a coil of coils; hence the name (Figure 3-10a). The individual helices bind tightly to one another because each helix has a strip of aliphatic (hydrophobic, but not aromatic) side chains (leucine, valine, etc.) running along one side of the helix that interacts with a similar strip in the adjacent helix, thus sequestering the hydrophobic groups away from water and stabilizing the assembly of multiple independent helices. These hydrophobic strips are generated along only one side of the helix because the primary structure of each helix is composed of repeating seven-amino-acid units, called heptads, in which the side chains of the first and fourth residues are aliphatic and the other side chains are often hydrophilic (see Figure 3-10a). Because hydrophilic side chains extend from one side of the helix and hydrophobic side chains extend from the opposite side, the overall helical structure is amphipathic. Because leucine frequently appears in the fourth positions and the hydrophobic side chains merge together like the teeth of a zipper, these structural motifs are also called leucine zippers.

Many other structural motifs contain α helices. A common calcium-binding motif called the EF hand contains two short helices connected by a loop (Figure 3-10b). This structural motif, one of several helix-turn-helix and helix-loop-helix structural motifs, is found in more than a hundred proteins and is used for sensing calcium levels. The binding of a Ca²⁺ ion to oxygen atoms in conserved residues in the loop depends on the concentration of Ca²⁺ in the cell and sometimes induces a conformational change in the protein, altering its activity. Thus calcium concentrations can directly control proteins’ structures and functions. Somewhat different helix-turn-helix and basic helix-loop-helix (bHLH) structural motifs are used for protein binding to DNA and, consequently, for the regulation of gene activity (see Chapter 9). Yet another structural motif commonly found in proteins that bind RNA or DNA is the zinc finger, which contains three secondary structures—an α helix and two β strands with an antiparallel orientation—that form a fingerlike bundle held together by a zinc ion (Figure 3-10c).

76

The relationship between the primary structure of a polypeptide chain and the structural motifs into which it folds is not always straightforward. The amino acid sequences responsible for any given structural motif in different proteins may be very similar to one another. In other words, a common sequence motif can result in a common structural motif. This is the case for the heptad repeats that form coiled coils. However, it is also possible for seemingly unrelated amino acid sequences to fold into a common structural motif, so it is not always possible to predict which amino acid sequences will fold into a given structural motif. Conversely, it is possible that a commonly occurring sequence motif will not fold into a well-defined structural motif. Sometimes short sequence motifs that have an unusual abundance of a particular amino acid, such as proline or aspartate or glutamate, are called “domains”; however, these and other short contiguous segments are more appropriately called “sequence motifs” than “domains,” as the latter term has a distinct meaning that we will define shortly.

We will encounter numerous additional motifs in our discussions of proteins in this and other chapters. The presence of the same structural motif in different proteins with similar functions clearly indicates that these useful combinations of secondary structures have been conserved in evolution.