2-7 Tertiary structure is the 3D structure of individual polypeptides

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• Tertiary structure is stabilized by hydrophobic interactions, hydrogen bonds, ionic interactions, and sulfhydryl bonds.
• Conserved tertiary structures are called motifs. There are many common motifs that have been discovered in many proteins. Some examples are ATP-binding and DNA-binding motifs.
• Structurally similar motifs imply a evolutionary relationship.
• Proteins are flexible, dynamic structures that respond to their surroundings.

The relationships mentioned above do not fully define the structure of proteins. For example, we need a way to describe larger organizations of α helices and β sheets, as well as other parts of proteins that do not fit these two patterns. This larger organization is termed tertiary structure.

As noted before, the most important stabilizing force in proteins is burying hydrophobic residues from the surrounding water, but there are other chemical features that are important in creating and stabilizing tertiary structure. These include hydrogen bonds, ionic interactions, and sulfhydryl bonds. Ionic interactions are attractions between groups of opposite charge. There are amino acids with negatively charged side groups (aspartate, glutamate) and amino acids with positively charged side groups (typically lysine and arginine). If opposite charges are brought close enough together, there will be an attractive force that can contribute to protein structure. It also follows that like charges repel each other and this can also dictate protein structure. Sulfhydryl linkages are covalent bonds between cysteine groups. Cysteine is a unique amino acid in that it has a sulfur group at the end of its variable side group that is available for binding to other groups. Often in proteins, nearby sulfhydryl groups on cysteines form a covalent bond and these are often crucial for the stabilization of the mature protein or for it to perform its function. Figure 2-13 shows some representations of sulfhydryl bond in proteins.

Figure 2-14 shows the tertiary structure of ribulose bisphosphate carboxylase (RubisCo), one of the most abundant enzymes on this planet. This enzyme takes energy, obtained most often from the sun, and uses it to convert carbon dioxide into carbohydrate. Its abundance reflects the fact that virtually all photosynthetic organisms, from bacteria to plants, use this enzyme to produce much of the cell's carbon. Note the α helices throughout the protein and the β sheet near the bottom. These structures help to hold the protein in its proper conformation so that it can carry out its enzymatic activity.

Now we have talked about certain secondary structures that recur in many proteins, but it also happens that there are conserved tertiary structures as well. In other words, there are regions of proteins, which are sometimes termed motifs or domains, that are structurally identical in two or more different proteins. Figure 2-15 shows some examples of protein motifs. By "structurally identical," we mean that they have similarly sized α helices and β sheets that are organized in a similar overall way. Interestingly, these domains typically do not have identical primary structures. Instead, it appears that a variety of different sequences can fold to give the same overall tertiary form. It is usually clear from the sequence that structurally similar domains from different proteins are evolutionarily related. That is, at one time there was a single protein with the domain and through evolution, an extra copy of the gene was created. Subsequent random mutations in each gene altered the primary sequences of the proteins, but the only changes that were tolerated were those that maintained the structure, and therefore the function, of each copy of the domain. This implies that these motifs often have a specific function. For example, there is a very common motif that proteins use for binding ATP. A second class of examples would be the set of motifs that are used to bind DNA. Through genetic changes, these motifs have been grafted onto other protein regions, so that the same ATP-binding (or the DNA-binding) domain performs a similar function for proteins with completely different overall activities. Of course the unique functions are defined by those portions of the protein that are not in common.

The existence of these conserved motifs was revealed by the analysis of the crystal structures of many different proteins. One saw similar structural regions performing similar functions in proteins that otherwise were quite dissimilar. Not surprisingly, since there are some residues that need to be conserved to form these structures, we can now predict some of these motifs based on the sequence of the proteins as well. The explosion of DNA sequence information and tools that can find these motifs has allowed the prediction of protein functions solely from sequences to be done with ever greater accuracy.

From this description you can see that proteins can often be looked at as a collection of "protein pieces," each of which serves a function and has an evolutionary history. We refer to these as functional domains. The enzyme pyruvate kinase, which generates ATP by removing it from phosphoenol pyruvate, has three domains, termed A, B and C. The A domain is responsible for binding substrate (phosphoenolpyruvate and ADP) while the C domain serves a regulatory role, binding fructose-6-bisphosphate and stimulating activity.

Up to this point, we have talked as if proteins are static rigid structures, but this is certainly wrong. Instead, most proteins are flexible, dynamic structures that respond to the conditions around them. Movement is typically essential to their function, especially for enzymes that need to grab a substrate, react with it and release product. In some cases, the flexibility is over very small distances; moving the residues of an active site just a few tenths of an angstrom (10^-10 meters) would have a major effect on binding and reacting with a substrate that is itself only a few angstroms in size. However, some protein movements are huge, where one domain changes its position relative to that of the rest of the protein. This obviously changes the tertiary structure of that protein. Thus, when we talk about tertiary structures, typically determined by crystallography, we are really referring to only one of the possible structures that the protein can exist in while performing its biological function. The structure we see through crystallography is simply the form of the protein that happened to form crystals and whose structure was then solved.

This flexibility has many important implications for a protein. At too high a temperature the protein might become too dynamic. This might overwhelm the stabilizing energy that maintains the protein, so that it unfolds or denatures. At too low a temperature, a protein might be so stable that it locks into a single structure and lacks the flexibility necessary to carry out its function. Interestingly, thermophilic microbes have been found to have more rigid proteins that can tolerate the turbulent environment of higher temperatures.

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