Proteins: Tertiary and Quaternary Structures

The tertiary structure of a protein is a description of the complex and irregular folding of the peptide chain in three dimensions. It is essentially a picture of what the shape of the entire protein actually looks like. Examples are shown in the following ribbon figure of human growth hormone.

The protein in these figure have easily discernable helices in particular areas, but that the entire three dimensional structure is more complex and irregular. In this figure, the helices are pink and the connecting amino acids are white. In order for growth homone to be active, it must have this particular conformation. If it should change at all, the activity of the protein will be lost. These complex structures is held together by a combination of several molecular interactions that involve the R-groups of each amino acid in the chain. Simplifying the physical chemistry, the structure of regions of peptide chains that do not form a regular secondary structure is determined by interactions between R-groups. These interactions include

  1. hydrogen bonds between polar R- groups
  2. ionic bonds between charged R-groups
  3. hydrophobic interactions between nonpolar R-groups
  4. covalent bonds: The R-group of the amino acid cysteine contains a sulfur atom and this sulfur atom is capable of forming a covalent bond with another sulfur atom on a different cysteine molecule somewhere else on the chain. This bond is known as a disulfide bond and it acts as to stabilize the tertiary structure of those proteins that have such bonds.

As was the case with the secondary structure, the tertiary structure can be altered by a number of factors that will interfere with the molecular processes that hold the structure together. For tertiary structure, these includes changes in temperature, pH, and ionic strength. Since the function of a protein is dependent on its structure and any factor that affects the structure will also affect the activity of the protein. Thus heating a protein can affect its structure and thus its activity.

The disruption of the protein structure (and thus its activity) by some "unnatural" condition (heat, pH, etc.) is known as denaturing the protein. Sometimes this denaturation is reversible, sometimes its not. For example, jello gels due to the presence of a "jello" protein. If you heat jello, you alter the structure of the protein so that it is no longer a gel but a liquid. If you reverse the denaturing conditions, that is, you cool it, the protein reforms into its original gel structure. (Some of you may know that you cannot make jello gel using fresh pineapple due to a proteolytic enzyme found in pineapple. If, however, one heats the pineapple, the enzyme is denatured and no longer breaks up proteins. The enzyme does not, however, renature to its natural structure when cooled, so it remains inactive and so cooked pineapple can be used to make jello.) Another common example of denaturation of proteins is egg white. Egg white is made up almost entirely of the protein ovalbumin. In its native state, the protein is in a liquid state but if heated, it forms a solid. Unlike jello, this transformation is irreversible (thank goodness, otherwise one would have to eat eggs very quickly!).

The importance of disulfide bonds in the structure of certain proteins is demonstrated by hair. Hair is made of the protein apha-keratin. The particular structure of your hair (straight, curly, etc.) is based on specific disulfide bonds that naturally form in the hair protein. This should help explain why an individual with straight hair cannot simply heat their hair, denature the protein (keratin), put in curlers and make it curly. The disulfide bonds are covalent bonds and thus are very strong. Heating these bonds will not break them, so simply heating hair will not change straight hair to curly. Instead, it is necessary to break these bonds chemically, reform the hair to the desired shape, and make new disulfide bonds to maintain the new shape. If an individual, therefore, goes to the hairdresser for a permanent, the beautician must first treat the hair with a reagent that reduces (and thus breaks) the disulfide bond (using the smelly stuff that makes me gag when I go by), then put in curlers (to get the desired shape), and add an oxidizing agent to form new disulfide bonds to maintain the new shape. Two major factors, however, are involved to ensure that a permanent is not really permanent. As the hair grows, the new hair will form the more stable, normal conformation. Also, since the new shape is not a "favorable" conformation, the new structure will put strain on the new disulfide bonds and will cause them to break more easily and the hair will slowly regain the old shape. Therefore, eventually, the new shape "grows out" and you must return again for another "permanent".

The quaternary structure of a protein describes the interactions between different peptide chains that make up the protein. Some proteins (such as hemoglobin) have more than one peptide chain (these are multimeric proteins). The manner in which these chains fit together (sort of like a puzzle) is the quaternary structure. Obviously, if a protein is made up of only one chain (monomeric), there is no quaternary structure for that protein. The forces that hold different chains together are the same that hold the tertiary structure together, hydrogen bonding between polar R-groups, ionic bonds between charged R-groups, hydrophobic interactions between nonpolar R-groups, and disulfide bonds. The figure below shows the structure of hemoglobin, a protein that has four subunits. Each subunit is identified with a different color. You should be able to identify secondary structure (alpha helix) as well as the tertiary structure of each subunit (how each one folds in space).

You should remember that the function (or the activity) of a protein depends upon the maintenance of the proper structure of the protein. The secondary, tertiary and quaternary structures, and therefore the activity, of a protein are as a direct result of the primary structure. This is most dramatically demonstrated in the genetic disease sickle cell anemia. The protein hemoglobin is made up of four polypeptide chains, two apha chains and two beta chains (biochemists love to call things by Greek letters). The beta chains of normal hemoglobin has the amino acid glutamate (a negatively charged R-group) in the sixth position. The chain from individuals with sickle cell anemia, however, has the nonpolar amino acid valine in the sixth position. The remainder of the 146 amino acids in the chain are the same in both individuals (as are the apha chains). This single change in the primary structure of the protein alters the structure of the hemoglobin so that it does not work correctly and causes severe anemia that can kill.

One of the major functions of proteins is to serve as enzymes. During this course, you will run into several enzymes, so it is important that you understand what they do and how they work.

Enzymes are catalysts. Catalysts are substances that act to speed up the rate of a chemical reaction. If you have ever had organic chemistry, you may remember adding platinum (or maybe some other metal) pellets to reaction mixtures. This was done to increase the rate of your reaction. The metal pellets act as catalysts.

Many thermodynamically permissible reactions are very slow thus they do not occur very quickly. For example, the paper that you are reading (if this was on paper, of course) is made of cellulose which you now know is a polymer of glucose. Glucose contains energy which is released when glucose is broken down (in the presence of O2) to CO2 and H2O. This is what happens when paper burns and it is what happens to glucose inside a cell. While this is thermodynamically a spontaneous reaction, I am confident that this paper will not burst into flames as you read it. Many reactions (such as this one) need help to get started. To burn paper, you must first add energy in the form of heat. Once the reaction is started, it will continue without needing any more energy input. The energy necessary to start a reactions is known as the activation energy for that reaction. This means that one way that one can increase the rate for a given reaction is to add energy in the form of heat. This is not a very practical method when one is talking about living systems as living things tend to die when they get too hot. So there is a problem, how can a cell burn glucose but not burn up? The answer lies with enzymes. Enzymes are proteins that act as biochemical catalysts. The primary function of an enzyme (and, in fact, of all catalysts) is to increase the rate of a reaction by decreasing the activation energy necessary for that reaction. Enzymes cannot make thermodynamically impossible reactions to occur, however, they simply increase the rate at which permissible reactions occur. Enzymes are different from inorganic catalysts (such as platinum) in that

  1. enzymes are very specific, each enzyme usually catalyzes only one reaction
  2. enzymes can be regulated (so that the reaction rate can be increased or decreased based on need)
  3. enzymes can be inhibited by a variety of conditions (including any condition that denatures the enzyme).

There is some terminology concerning enzymes that you should know. The activity of an enzyme is a measurement of how fast the enzyme is catalyzing its reaction. If the activity of an enzyme is increased, it is catalyzing the reaction at a faster rate. Now assume the following is an enzymatic reaction: In this reaction, A reacts with B to form C and D in the presence of an enzyme. The reactants of the reaction, A and B, are known as the substrates for the enzyme and the C and D are known as the products.

Let us look at an example of an enzyme. The following reaction is catalyzed by the enzyme glycogen phosphorylase: Essentially, this enzyme catalyzes the breakdown of glycogen ((glucose)n) one glucose at a time and yields glucose 1-phosphate and a glycogen molecule that has one fewer glucose molecules on the chain. This reaction is used during times of fasting when the body needs to use stored reserves of glycogen to produce glucose. You might guess that this reaction is not needed when one is feeding (such as eating a bag of M&M's). During this latter instance, the body has plenty of glucose and would actually want to store the excess in the form of glycogen and would want to turn off glycogen phosphorylase during this time. This is done in the following manner: there is an enzyme (called phosphorylase kinase) in cells that is capable of adding 4 phosphate groups (PO4- or Pi) to glycogen phosphorylase. A phosphate group has a charge of -3. The addition of such highly charged groups onto the enzyme causes a change in the structure of the protein which results in a change in the activity of the enzyme as well (remember the relationship between the structure and function of proteins). The phosphorylated from of glycogen phosphorylase is more active than the unphosphorylated form, thus the addition of the phosphate acts as a switch to increase the activity of glycogen phosphorylase. Now, would you expect glycogen phosphorylase to be phosphorylated during eating or fasting? Why do you think so?

Some things to remember about turning on and off enzymes:

  1. when enzymes are physiologically turned off they usually can still act as enzymes but at a slower rate
  2. adding a phosphate group to an enzyme is not the only way the activities of enzymes can be controlled. Each enzyme is controlled by some mechanism specific for that enzyme. Phosphorylation is one example of a regulatory mechanism.

For more information on enzymes, please go here.

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