Unit 2a. Proteins: Structure and Action

BIOCHEMISTRY FOR CITIZENS

Molecular machines

Proteins are the central machinery in a cell. There are thousands of different proteins, all built from 20 different building blocks (called amino acids) linked into long chains. As building blocks are linked in the appropriate order (after which, they are called residues), the resulting chains fold into compact structures that function as molecular machines. Among these machines are enzymes, antibodies, transporters, hormones, and mechanical proteins of muscles.

Let’s take a closer look at a protein chain. Below is a chain of nine amino-acid residues, like a fragment of a typical protein. In a full protein model, the chain would continue from the ends in both directions.

Nine residues of a protein chain.

Notice a continuous horizontal chain of atoms, starting at the left with nitrogen (blue, N), then carbon (white, C), then another carbon with a single oxygen (red) attached (CO, also called carbonyl), and then eight more repetitions of the same sequence (N, C, CO, N, C, CO), ...). This is called the protein backbone. From the backbone extend branches of atoms called side chains, always connected to the middle C atom. One amino-acid residue comprises one repeat of N, C, CO, including the side chain on C. Proteins typically contain a few hundred residues, but the full range is from a handful of residues to more than a thousand.

The same nine residues with arrows to represent backbone.

Each protein has a unique sequence of residues specified by its gene, which is a segment of DNA in the nucleus that gives the recipe for the protein (for more on the relationship between genes and proteins, see Unit 3).

The folded, functional form of a protein is called its native state. Common folding patterns in proteins include helix (screw-like), sheet (parallel chains), and loop (any old shape). Below, you see some ways in which scientists represent amino acids and proteins. Each type of model emphasizes different aspects of a molecular structure. All images are models of cytochrome b5, a liver protein involved in removing toxic substances from the body. Clockwise from top left are a) one amino acid residue in ball-and-stick model (B&S); b) same, in a space-filling (SF) model (shows atoms with correct relative size); c) whole protein, B&S; d) same, SF; e) same, ribbon model (shows the continuity of the protein chain). Red segments of ribbon are helices, yellow are strands of sheets. Heme, a non-protein part essential to the function of cytochrome b5, is shown B&S. It binds to the protein by weaker bonds, much like those that bind water in snowflakes.

Various models of the same protein.

Some examples of protein function

Example #1: hemoglobin—transporting oxygen from lungs to organs

The protein hemoglobin, which is plentiful in red blood cells, picks up molecules of oxygen (chemical formula O2) as blood passes through the lungs, and transports it to all parts of the body. Blood containing red blood cells and hemoglobin can carry about 70 times as much O2 as can water or blood without hemoglobin.

Hemoglobin comprises four protein chains, two called alpha, two called beta. The two different chains in hemoglobin are members of a protein family, a large group of similar proteins called globins. The image below is a ribbon model of a hemoglobin molecule, with each of the four chains shown in a different color. Each chain can carry one oxygen molecule.

Ribbon model of hemoglobin, its four protein chains in different colors.

The next image provides a closer look at the green chain and its active site, where it carries oxygen. A molecule of O2, the two connected red atoms in the center, is shown, with dotted green lines representing attraction to a nearby amino-acid side chain. Part of the active site is a heme (shown edge-on in ball-and-stick), just like the one in cytochrome b5. In the center of the heme is an iron ion (silver). The right-hand O of O2 is shown covalently bonded to the iron.

Close-up of one heme with bound oxygen molecule (two connected red atoms).

Carbon monoxide (chemical formula CO), a product of incomplete burning of fuels, is a toxic gas, and it is toxic for a simple reason. A molecule of CO is very similar to O2 in size and shape, and can bind to hemoglobin in about the same way that O2 does, but much more tightly. If there is even a small amount of CO in the air, hemoglobin picks up CO molecules in the lungs, and cannot let it go, greatly reducing oxygen transport. The result is suffocation, even in the presence of plenty of oxygen.

Example #2: antibodies—recognizing intruders

Living organisms have many lines of defense against invasion by foreign organisms (bacteria, viruses, fungi) or substances (toxins). One is the immune system, which is a vague term describing a very complex system of cells and proteins that recognize and dispose of several kinds of intruders. (The term immune system is so vague that the European Food Safety Agency [EFSA], which has many of the functions of the FDA and USDA in the US, does not permit foods or supplements to be labeled with such claims as “strengthens the immune system”, which, in the US, is a common claim, even though it is meaningless)

The primary recognition function of the immune system is carried out by large proteins called antibodies. Your body contains thousands of antibody-producing cells, each capable of producing one specific type of antibody that can recognize a very limited range of similar foreign substances, called antigens.

The nature of antibody-antigen binding is an important subject of study, because it guides scientists in developing vaccines, which consist of either 1) specially made antibodies, or 2) foreign substances (like a harmless part of a harmful organism) that will stimulate the production of appropriate antibodies.

A model of one type of antibody, immunoglobulin G (IGG), is shown below. IGGs consist of four protein chains, two “heavy” and two “light”. In the image, heavy chains are green and red, and light chains are yellow and purple. Each heavy chain consists of four compact protein folds, like four beads on a string, and each light chain has two such beads. All 12 beads are folded approximately the same way, into barrels of pleated sheets, 9 strands in each barrel.

Immunoglobulin G (IGG), an antibody. IGGs comprise four chains, two “heavy” (H, red and green),and two “light” (L, yellow and purple). The arrows indicate the locations of  antigen-binding sites.

The two beads of each light strand stick (bind noncovalently) to two beads of a heavy chain to form compact units (green+yellow and red+purple), each constituting an antigen-binding site. So each antibody has two identical antigen-binding sites, shown by the black arrows.

A single antigen-binding site is shown below, along with an antigen (space-filling) and the amino-acid side chains (ball-&-stick) that constitute the pocket into which the antigen fits. Note that only a few side chains interact with the antigen, but the pocket fits the antigen like a glove.

An antigen’s-eye view of an antibody, looking directly into the antigen binding site at the upper right of the previous figure. Antigen is space-filling, side chains of antibody are B&S.

Antibodies stick to antigens by weak bonds such as hydrogen bonds, the same bonds that hold water molecules together in snowflakes. As stated above, your immune system can produce antibodies that will recognize any imaginable chemical structure.

When a foreign substance enters your body and is recognized by an antibody, the binding of antigen to antibody triggers rapid cell division and proliferation of just those cells that make that particular antibody. Some of these new cells pump out additional antibodies to neutralize the antigen and mark it for disposal. But some of the new cells, called memory cells, become quiescent and provide a reserve of antibody production for future invasions. The result is that the first response to an new antigen is somewhat slow, because only a small number of cells producing the appropriate antibody are present. Thus some symptoms of the invasions might appear before the immune response can remove the invader. But subsequent invasions are met with a faster response, as a result of the action of plentiful memory cells. In many cases, the invader is removed before any symptoms appear.

A curious little thing about biomolecules: they can be left- and right-handed.

Amino acids, the building blocks of proteins, are relatively simple in structure. All 20 of the common amino acids have a central carbon, to which are attached four components: a hydrogen atom (-H), an amine group (-NH3+), an acid group
(-COO—), and a variable group (-R, called, in a protein, the side-chain). The 20 different amino acids differ only in the variable group R. (R stands for radical, an older term that refers in this context to a fragment having unspecified composition). In an amino-acid residue of a protein, the atoms of the N, C, CO sequence are derived, respectively, from the amine, central carbon, and CO of the acidic group.

Left- and right-handed forms of the amino acid threonine.

But there is an added twist to the structure of amino acids, and to any molecules in which one carbon, like the central carbon of threonine, carries four different groups of atoms. There are actually two different ways to put four different groups onto one atom.

Hold your right hand up to a mirror, and you will see a left hand reflected back at you. Now think of your two hands as mirror images, and try to superimpose them, thumb on thumb, pinky on pinky, front on front, back on back—that is, both hands facing the same direction. You can either put thumb on thumb, or have both hands facing the same direction, but not both. Your hands are, roughly, mirror images that cannot be superimposed. Chemists call objects like this enantiomers, which is a mouthful, but it’s still easier than calling them non-superimposable mirror images. One simple type of enantiomer is a molecule in which a central atom carries four different groups of atoms, as in most amino acids.

Many biological molecules, including most amino acids, sugars, and fats, come in enantiomeric forms. It might surprise you to learn that only one of the two forms of each is common in nature. The left-handed form of amino acids is by far more common than the right-handed forms. During photosynthesis, plants make only the right-handed form of the common sugar glucose. Only the right-handed forms of sugars, and only the left-handed forms of amino acids, are nutritious to animals and plants.