Levels Of Protein Structure

The most fundamental form of each DNA, RNA, and protein is a stringlike chain of smaller molecules. The word molecule will be used throughout this book to talk about assemblies of atoms of various sizes. (There are more specialized names for molecules, such as peptides or polypeptides, but for the purposes of the book, molecules will do.)

In proteins the basic units are called amino acids. Evolution has produced 20 types of amino acids, which are assembled in the cell by other molecules or derived from food and then strung together. Every organism needs all 20 types of amino acid, but not every organism can make them all. Human and animal cells, for example, are unable to make the amino acid leucine, so people have to obtain it through their diet. (It is easy to obtain, by eating other proteins.) On the other hand, the bacterium that causes tuberculosis cannot obtain leucine externally and has to make its own. A group of researchers called the X-MTB consortium, based in Hamburg and Berlin, Germany, hope to use this fact to fight tuberculosis. They are currently trying to make drugs that will interfere with the bacterium's leucine-making machine. Such a drug might kill the bacterium without damaging the cells it has infected. According to Manfred Weiss, who heads the project at a station of the European Molecular Biology Laboratory in Hamburg, "A laboratory strain of tuberculosis that cannot manufacture leucine does not reproduce when it invades human cells. To reduce the potency of the bacteria, it may be enough to block a single step in the leucine synthesis machinery."

Amino acids are small clusters containing from about nine to 30 atoms. At the core of each type is a carbon atom, which binds to other atoms on four sides. In one direction there is always a hydrogen atom. On the second side there is a unit called an "amino group" (one atom of nitrogen bound to two atoms of hydrogen). On the third is a "carboxyl group," made of one atom of carbon, two of oxygen, and one of hydrogen. A group of atoms called the "side chain" forms on the fourth side; what is found there makes each amino acid unique.

A protein consists of a long string of amino acids connected to each other in a specific order, like the letters that make up this sentence. Amino acids bind to each other when the car-boxyl group of one links to the amino group of the next. The process of binding releases a molecule of water and leads to the formation of a peptide bond. Adding water can make the amino acids release each other again. This could happen naturally, by itself, but it would take a long time—about a thousand years if the molecule were left alone in water. The process can be sped up by enzymes that break the bonds and thus free parts of the molecule to interact in new ways. By doing so, enzymes drive the chemistry of the cell.

The information in a gene shows the cell how to make a protein by telling it which amino acids to use and which order to put them in. After that, chemical bonds form between the amino acids to create many types of folds and structures, sometimes with the help of partner molecules. The following four different levels of structure have to be considered to understand how molecules work together:

• Primary structure is the string, the linear "spelling" of a protein, the list of amino acids in the order in which they are connected by peptide bonds.

• Secondary structure forms because the amino acids that lie near each other in the string chemically attract each other and create small folds. This usually produces one of two shapes, a coil called an alpha helix or a flat beta strand. Strands often lie next to each other and link to each other in larger beta sheets. Secondary structures are usually linked to each other by loose parts of the string known simply as "linkers."

• The surfaces of helices and coils may easily bind to other parts of the protein because their atoms also lack electrons. Tertiary structure arises when the secondary structures attract each other and fold into larger modules called domains. The result is to hide some amino acids in the interior and leave others exposed on the outside where they can interact with other domains or molecules. A protein may have several such modules, connected by loose, linking strands. This gives the protein a specific three-dimensional shape that plays an important role in its functions. These shapes are often tight and can only be changed by physical force or by a significant change in the domain's chemistry that breaks some bonds and allows others to form.

• The outer surface of a complete protein with all of its domains can bind to other molecules to create quaternary structure. Such "machines" composed of multiple proteins (or combinations of proteins, RNA, DNA, or other molecules) carry out most of the work in a cell.

As the primary amino acid string folds into these larger levels of structure, its shape and chemistry become so specific and complex that it can usually only bind to a few partners and sometimes only one. This keeps the wrong molecules from combining and is the main reason that tens of thousands of different molecules are able to organize themselves into the precise, long-lasting structures that make up a cell.

Primary structure

(amino acid string)

Secondary structure

(beta sheets and alpha helices)

Tertiary structure


Quarternary structure

(interaction between domains of one or more proteins)

G Infobase Publishing

Quarternary structure

(interaction between domains of one or more proteins)

How these levels work together is exemplified in a protein machine known as an exosome, whose job is to break down RNA molecules that have become defective or are no longer needed.

(opposite page) A protein consists of a string of amino acids (primary structure). Chemical interactions between its subunits cause it to fold into small alpha helices or beta sheets (secondary structure), that form larger domains that determine the protein's functions (tertiary structure).

An exosome consists of 11 main proteins: It has a core made of six of the proteins, which dock onto each other to form a ring. The chemistry of this ring allows it to break the bonds between nucleotides, the subunits of an RNA molecule. The other proteins in the exosome help position an RNA and maneuver it into the core, putting it into contact with the ring proteins that break it down.

Some proteins bind to each other for long periods of time and make very stable machines. Others link only briefly to carry out a job; then the machine is taken apart again, and the pieces are reused to do other things. In 2002, researchers in Heidelberg, Germany, discovered how truly dynamic this situation is. Anne-Claude Gavin and Giulio Superti-Furga of the biotech company Cellzome worked with scientists at the European Molecular Biology Laboratory to capture the first complete view of the machines at work in a yeast cell. They found that 17,000 proteins form at least 232 machines. Many of them work in a "snap-on" way; they have a core of preassembled pieces, and when it comes time to do a certain job, a few more are added on. A machine may remain inactive until that happens. This gives the cell a way to control its activity. To be switched on, it may need to borrow the missing pieces from other protein complexes, or components may have to be made anew.

For example, one job of a protein called beta-catenin is to transmit instructions to several genes. When they are activated, the cell produces new molecules that can dramatically change its behavior. Because the instructions should only be transmitted at certain times, beta-catenin usually has to be kept switched off. The cell manages this by attaching other molecules to it. These molecules prevent beta-catenin from moving to the nucleus— which it has to do to activate genes—and they also call up other machines that break it down. When the cell's behavior needs to change, beta-catenin is attached to other molecules that deliver it to the nucleus.

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