Module 2 - Lesson 1 Amino Acids

Question 1

How do faulty protein structures lead to disorders such as Alzheimer’s disease?

Answer 1

The neurodegenerative effects of Alzheimer’s disease are clearly visible when comparing scans of the brain of an Alzheimer’s disease patient (right) and a normal brain (left). The red and yellow colors represent areas of high and medium blood flow, respectively. Consistent with the presence of diseased tissue, the diseased brain clearly has less blood flow than the normal brain.

Question 2

about proteins

Answer 2

The molecules we call proteins play many key roles in living systems. Some proteins form building materials from which larger structures are formed. Your hair, fingernails, and tendons, for example, are made primarily of protein molecules. Proteins also serve as the receptors in the cell membrane that control what goes in and out of each cell in your body. Proteins play many specialized roles in our bodies—for example, as hormones that regulate bodily functions or as antibodies that protect against disease and infection. Additionally, proteins serve as enzymes, which control the rate of many chemical reactions and processes in living things. Indeed, proteins play a major role in almost every cellular function in your body.

Question 3

animation: protein refresher

Answer 3

Despite the fact that there are only 20 different amino acids from which proteins are made, the diversity in proteins is incredibly large. How is this possible? Imagine that amino acids are different types of LEGO® bricks - with 20 possible options available for each brick choice, the combinations allow you to build anything you can imagine. Now let’s take a closer look at these 20 amino acids.

Question 4

Proteins Are Chains of Amino Acids

KEY CONCEPTS

Answer 4

All amino acids share a common backbone structure with a carboxyl group, amino group, and side chain (“R” group) attached to a central carbon.
The 20 amino acids differ in the chemical characteristics of their R groups.
Amino acid R groups can be hydrophobic (nonpolar), polar, or charged.
Amino acids are linked by peptide bonds to form a polypeptide.
The exact amino acid sequence is the primary structure of a protein and gives the proteins its unique identity and characteristics.
Just as nucleic acids (DNA and RNA) are polymers of nucleotides, proteins are polymers of amino acids. An amino acid is a small molecule containing an amino group (–NH3+), a carboxyl group (–COO_), and a side chain of variable structure, called an R group. These three groups are all bound to a central carbon known as the alpha carbon. This common structure of all amino acids is known as the amino acid backbone (Figure 2-3).

Question 5

The 20 Amino Acids Have Different Chemical Properties

Answer 5

A cell has 20 “standard” amino acids that are commonly found in proteins. The identities of the R groups distinguish the 20 standard amino acids from one another. The R groups can be classified by their overall chemical characteristics as hydrophobic (nonpolar), polar, or charged, each of which we will examine in more detail. It is important to understand how the different types of amino acid side chains form different types of interactions because it is the combination of these interactions that determine the three-dimensional structure of proteins.

Question 6

The Hydrophobic Amino Acids

Answer 6

As their name implies, the hydrophobic amino acids have nonpolar side chains (highlighted in blue below). These side chains contain mostly nonpolar C-C and C-H bonds that cannot form hydrogen bonds. As a result, they interact very weakly or not at all with water, and try to avoid water whenever possible (“hydro” = water and “phobic” = fear/hate of).

Question 7

The Polar Amino Acids

Answer 7

The side chains of the polar amino acids (highlighted in yellow below) can interact with water because they contain hydrogen-bonding groups, including OH, NH, and SH. These amino acids are often found on the water-exposed surface of a protein, although they can also occur in the protein interior.

Question 8

The Charged Amino Acids

Answer 8

Four amino acids have side chains (highlighted in pink below) that are virtually always charged under physiological conditions. Aspartate (Asp) and glutamate (Glu), which bear carboxylate groups, are negatively charged. Lysine (Lys) and arginine (Arg) are positively charged. These side chains are usually located on the protein’s surface, where their charged groups can be surrounded by water molecules or interact with other polar or charged substances.

Question 9

Peptide Bonds Link Amino Acids in Proteins

Answer 9

Recall, from Module 1 on Nucleic Acids, that proteins are made by the ribosome. The ribosome links amino acids together with a specific type of bond called a peptide bond. Because proteins are made up of many amino acids bonded together by peptide bonds, a single protein chain is called a polypeptide (“poly” = many). The formation of a peptide bond involves the dehydration of the carboxyl group (–COO_) of one amino acid and the amino group (–NH3+) of another amino acid (a dehydration reaction is one in which a water molecule is removed).

Question 10

The Amino Acid Sequence is the First Level of Protein Structure

Answer 10

The sequence of amino acids in a polypeptide is called the protein’s primary structure (Fig. 2-9). This order of amino acids gives a protein its identity because it is unique from the amino acid sequence of other proteins. Recall that the order of amino acids is determined by the nucleotide sequence of the gene that encodes the protein, so each gene gives rise to at least one protein with a unique amino acid sequence (and sometimes more if alternative splicing takes place).

Question 11

Levels of Protein Structure

KEY CONCEPTS

Answer 11

Primary structure is the order of amino acids in a protein. The amino acids are held together by peptide bonds and do not change.
Secondary structure is the localized shape that is formed by hydrogen bonding patterns of amino acid backbone atoms. The most common secondary structures are the alpha helix and beta sheet.
Tertiary structure is the result of different secondary structures interacting with one another via their R groups. These interactions include hydrophobic interactions, hydrogen bonds, ionic bonds, and disulfide bonds.
Proteins with more than one polypeptide have quaternary structure, and the polypeptides are held together by R group interactions similar to those that stabilize tertiary structure.
Proteins can be denatured by disrupting the interactions that contribute to secondary, tertiary, and quaternary structure.

As discussed in the previous chapter, each protein has its own unique sequence of amino acids that determine its chemical properties and behavior. The interactions of these different amino acids are what determine the overall three-dimensional structure of a protein. A protein’s structure is usually ascribed three or four stages, or levels, each representing an increasing order of complexity (Figure 2-2).

Question 12

Levels of Protein Structure

KEY CONCEPTS

Answer 12

Primary structure is the order of amino acids in a protein. The amino acids are held together by peptide bonds and do not change.
Secondary structure is the localized shape that is formed by hydrogen bonding patterns of amino acid backbone atoms. The most common secondary structures are the alpha helix and beta sheet.
Tertiary structure is the result of different secondary structures interacting with one another via their R groups. These interactions include hydrophobic interactions, hydrogen bonds, ionic bonds, and disulfide bonds.
Proteins with more than one polypeptide have quaternary structure, and the polypeptides are held together by R group interactions similar to those that stabilize tertiary structure.
Proteins can be denatured by disrupting the interactions that contribute to secondary, tertiary, and quaternary structure.

As discussed in the previous chapter, each protein has its own unique sequence of amino acids that determine its chemical properties and behavior. The interactions of these different amino acids are what determine the overall three-dimensional structure of a protein. A protein’s structure is usually ascribed three or four stages, or levels, each representing an increasing order of complexity (Figure 2-2).

Question 13

Primary Structure

Answer 13

The exact sequence of amino acids that go into a given protein is called its primary structure. Every distinct protein has a different primary structure; that is, it has a different sequence of amino acids.

Question 14

Secondary Structure

Answer 14

Depending on the arrangements of amino acids in the primary structure, hydrogen bonds can form between backbone atoms that give that localized portion of a protein a specific shape. These specific, localized shapes taken by the backbone of the polypeptide chain are called its secondary structure. The most common secondary structure shapes include alpha helices, often represented by spirals, and beta pleated sheets, which are sometimes shown as pleats but more often by flat arrows (Figure 2-4).

Question 15

Tertiary Structure

Answer 15

As the secondary structural elements of the polypeptide chain fold back on themselves, atoms in the R groups can come into contact with each other. As a result, additional chemical interactions and bonds form between the R groups of amino acids in different parts of the chain. As a result of these interactions, a protein will twist around, bend, kink, and fold itself into a complex shape, much as a string will fold itself into a complex shape when dropped on a table. This complex folding is the tertiary structure of the protein. The final shape of the protein, as determined by its tertiary structure, is critical to its proper functioning. Many human diseases, including sickle cell anemia, some forms of arthritis, and hemophilia, occur when proteins fail to folder properly.

Question 16

Quaternary Structure

Answer 16

Finally, two or more polypeptides, each with its own secondary and tertiary structure, may come together to form a single, larger unit. This joining of separate protein chains determines the quaternary structure of the protein. A protein with quaternary structure may have two polypeptides or as many as a dozen different protein chains in its final, active form. Each polypeptide chain that is part of a larger protein is referred to as a subunit. The subunits that make up the quaternary structure of a protein can be different or identical polypeptides, and sometimes a mix of both. Hemoglobin, for example, has a total of four subunits: two alpha subunits that are identical to one another and two beta subunits that are identical to each other but different from the alpha subunits (Figure 2-6).

Question 17

R Group Contributions to Protein Structure and Stability

Answer 17

As discussed in the chapter on amino acids, each of the 20 common amino acids belongs to one of three general groups: hydrophobic, polar, or charged amino acids. Each of these groups contribute characteristic interactions to protein stabilization.

Question 18

Protein Structures Are Stabilized Primarily by the Hydrophobic Effect

Answer 18

The phrase “oil and water don’t mix” is an example of the hydrophobic effect. Recall that hydrophobic groups (such as oil) cannot form hydrogen bonds with water and therefore try to associate with water as little as possible. The largest force governing protein structure is the hydrophobic effect, which causes hydrophobic R groups to cluster together in the interior of a protein in order to minimize their contact with water. This arrangement stabilizes the folded polypeptide backbone, since unfolding it or extending it would expose the hydrophobic R groups to water (Figure 2-7).

Question 19

Hydrogen Bonding

Answer 19

Hydrogen bonding by itself is not a major contributor to protein stability because the R groups of polar amino acids can form hydrogen bonds with water or with other amino acid side chains equally well and therefore don’t need the protein to be folded to allow them to make those interactions. Instead, hydrogen bonding can help the protein fine-tune a folded conformation that is already largely stabilized by the hydrophobic effect.

Question 20

Ionic Bonds

Answer 20

An ionic bond (sometimes called a salt bridge or ion pair) can form between oppositely charged side chains of the charged amino acids. Although the resulting ionic bond between the positive and negative charges is strong, it does not contribute much to overall protein stability. Instead, like hydrogen bonds, ion bonds help to fine-tune the tertiary and quaternary structure of a protein.

Question 21

Disulfide Bonds

Answer 21

Recall that the R group of cysteine contains a thiol (SH) group that can form a very strong covalent link known as a disulfide bond. Disulfide bonds form when two cysteine R groups are in close proximity and the two sulfur atoms form a covalent bond between them. The covalent cross-link formed by disulfide bonds is especially common in proteins that are secreted from the cell, such as insulin, and proteins that serve a more structural purpose, such as the keratin protein found in skin, hair, and nails.

Question 22

Metals Ions Can Contribute to Protein Structure

Answer 22

In addition to the interactions of R groups, some proteins also use metal ions, such as zinc or iron, to stabilize and refine protein structure. The metals are generally found near the center of the protein, where they form metallic bonds with atoms of various polar side chains (Figure 2-8).

Question 23

video

Answer 23

Watch this video to review the levels of protein structure and the ways that amino acid side chains contribute to tertiary structure.

Question 24

Proteins Can be Denatured

Answer 24

Thus far, we have discussed how protein structure can be stabilized by several factors, the most significant of which is the hydrophobic effect. We now turn our attention to the factors that can disrupt protein stability and structure. This process is called denaturation, and a protein whose native (functional) structure has been disrupted significantly is said to be denatured. Denaturation is the loss of a protein’s native (functional) three-dimensional structure due primarily to the loss of tertiary structure; it is not the breaking of peptide bonds. Denatured proteins retain their primary structure, but lose their ability to function normally due to disruption of the higher levels of structure.

Just as protein structure is stabilized primarily by the hydrophobic effect, disruption of the hydrophobic effect is the simplest way to denature a protein. This is generally done by applying heat. High temperatures cause the atoms in a protein to move so quickly that the structure loosens and causes the hydrophobic core to open up and expose the nonpolar residues to water. This drives the hydrophobic regions of the protein to seek out anything nonpolar, and the proteins will begin clumping together in a disorderly way to form an insoluble, solid mass of protein (recall that insoluble means it cannot be dissolved by water).

Question 25

Protein Folding and Disease

KEY CONCEPTS

Answer 25

Protein folding follows a process and can be assisted by chaperones to ensure proper folding. Some proteins have more than one stable conformation.
Misfolded proteins are usually degraded by the cell to avoid problems. If they are not degraded, misfolded proteins can aggregate and contribute to disease.
The formation of amyloid fibers or amyloid plaques are a common theme among different neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease.
The crowded nature of the cell interior demands that proteins and other macromolecules assume compact shapes. In the cell, a newly synthesized polypeptide begins to fold as soon as it emerges from the ribosome, so part of the polypeptide may adopt its mature tertiary structure before the entire chain has been synthesized. Protein-folding experiments demonstrate that protein folding is a process that happens in stages. During this process, small elements of secondary structure form first, then these cluster under the influence of the hydrophobic effect to produce a mass with a hydrophobic core. Finally, small rearrangements by R groups (i.e., hydrogen bond and ionic pair formation) yield the native (functional) tertiary structure (Fig. 2-20).

Question 26

Some Proteins Have More Than One Structural Conformation

Answer 26

Some proteins can adopt more than one conformation. A protein’s native structure is not necessarily rigid and inflexible. In fact, some minor movement, primarily the result of bending and stretching of individual bonds, is required for most proteins to carry out their biological functions. In some cases, a protein’s conformational flexibility includes two stable alternatives that constantly interconvert back and forth between the two possible structures. A change in cellular conditions, such as pH or oxidation state, or the presence of a protein binding partner, can tip the balance toward one conformation or the other (Fig. 2-21). This ability of one protein conformation to bind and influence the protein conformation of another protein is an important aspect in the progression of some diseases, as discussed below.

Question 27

Protein Misfolding and Disease

Answer 27

At the start of this lesson, we posed this question, How do faulty protein structures lead to disorders such as Alzheimer’s disease? The answer lies in the cell’s failure to deal with misfolded proteins. Normally, the chaperones that help new proteins to fold can also help misfolded proteins to refold into the correct structure. If the protein cannot be salvaged in this way, it is usually degraded to its component amino acids. This quality control system explains what happens in the most common form of cystic fibrosis: a mutated form of the CFTR protein folds incorrectly, is degraded, and therefore never reaches its intended cellular destination.

Question 28

Alzheimer’s Disease

Answer 28

Alzheimer’s disease, the most common neurodegenerative disease, is accompanied by both intracellular tangles and extracellular plaques (sometimes called “senile plaques”), both of which are the result of abnormal protein aggregation (Figure 2-12). The fibrous material inside cells is made of a protein called Tau, which is involved in the assembly of microtubules, a component of the neuron cytoskeleton. In Alzheimer’s disease, the Tau becomes defective and form filaments in the neuron. The loss of the cytoskeleton ultimately causes the neuron to die, and the filaments of Tau cause the neurofibrillary tangles that are characteristic of the disease. Tau deposits also appear in some other neurodegenerative diseases, and tau’s role in Alzheimer’s disease is not yet clear.

Question 29

Parkinson’s Disease

Answer 29

In Parkinson’s disease, neurons in a portion of the brain accumulate fragments of a protein known as alpha-synuclein. Like amyloid-beta, alpha-synuclein’s function is not fully known, but it appears to play a role in neurotransmission. Alpha-synuclein is a small protein (140 amino acid residues) with an extended conformation, part of which appears to form alpha helices upon binding to other molecules. The intrinsic disorder of the protein may contribute to its propensity to form amyloid deposits, which are characterized by a high content of beta secondary structure. Accumulation of this material is associated with the death of neurons, leading to the typical symptoms of Parkinson’s disease, which include tremor, muscular rigidity, and slow movements. Mutations in the gene for alpha-synuclein that lead to increased expression of the protein or promote its self-aggregation are responsible for some hereditary forms of Parkinson’s disease.

Question 30

Transmissible Spongiform Encephalopathies (TSEs)

Answer 30

Mad cow disease is the best known of the transmissible spongiform encephalopathies (TSEs), a group of disorders that also includes scrapie in sheep and Creutzfeldt–Jakob disease in humans. These fatal diseases, which give the brain a spongy appearance, were once thought to be caused by a virus. However, extensive investigation has revealed that the infectious agent is a protein called a prion. Interestingly, normal human brain tissue contains the same protein, named PrPC (C for cellular), which occurs on neural cell membranes and appears to play a role in normal brain function. The scrapie form of the prion protein, PrPSc, has the same 253–amino acid sequence as PrPC but includes more beta secondary structure. Introduction of PrPSc into cells apparently triggers PrPC, which contains more alpha-helical structure, to assume the PrPSc conformation and thereby aggregate with it (Figure 2-13).

Question 31

Changes in Protein Structure Lead to Amyloid Deposits

Answer 31

Despite the lack of sequence or structural similarities among amyloid-beta, alpha-synuclein, and PrPSc, their misfolded forms are all rich in beta secondary structure, and this seems to be the key to the formation of amyloid deposits. Studies of a fungal polypeptide similar to PrPSc show how amyloid formation might occur. In its original state, the protein is mostly alpha-helical. A segment of polypeptide shifts to an all-beta conformation, which allows single molecules to stack on top of each other in parallel to form a triangular fiber stabilized by hydrogen bonding between the chains. In this model, five aggregated polypeptides are shown. The vertical arrow indicates the long axis of the amyloid fiber.

Question 32

LESSON REVIEW

Answer 32

A protein is translated into a primary sequence of amino acids, bound together by peptide bonds. The function and structure of a protein are dictated by the R groups of these amino acids. The 20 different R groups can be classified as hydrophobic, polar, or charged. The backbone atoms of the polypeptide chain will make hydrogen bonds that form the protein’s secondary structure—usually alpha helices or beta sheets.

The R groups of the amino acid residues project out from the secondary structures and can interact with the R groups of other amino acids in the polypeptide to form the protein’s tertiary structure. The most important contributor to protein stability is the hydrophobic effect, including the hydrophobic interactions made between nonpolar R groups. The other R group interactions—hydrogen bonds, ionic pairs, and disulfide bonds—are less influential on protein stability, but they do contribute to the final, finely tuned structure of a protein, as well as its function. Metal ions can also be used to form and stabilize tertiary structure. The same R group interactions can also be used to hold multiple polypeptides, or subunits, together in a protein with quaternary structure. Disruption of these interactions can denature, or unfold, a protein’s three-dimensional structure, which causes it to lose its function as well.

Protein folding is the process by which the primary structure takes on its final three-dimensional shape. As the polypeptide is coming out of the ribosome, some of the secondary structure can begin to form, and chaperone proteins will often help the newly emerging protein to fold properly. The secondary structures then coalesce together to form the final tertiary structure of the polypeptide. Any problems in the folding process can lead to a misfolded, nonfunctional protein that is usually degraded by the cell. However, sometimes misfolded proteins persist and begin to aggregate as a result of their hydrophobic residues being exposed to water. A particular type of protein aggregation, known as amyloid fibers or plaques, is associated with a number of neurodegenerative diseases, including Alzheimer’s disease.

How well do you understand the Lesson 1 material? Click on the Module 2 Check Your Understanding: Protein Structure to take the short self-quiz.

Deedra now has a solid understanding of the basic biochemical basis for her father’s disease: he has protein aggregates of amyloid-beta and Tau protein causing damage to his neurons. She now wants to learn more about the treatment prescribed by the doctor, and how it may help her father’s symptoms.