The primary structure of a protein, which is its amino acid sequence, determines its unique three-dimensional structure known as the native conformation. This native conformation is essential for the protein to function properly, whether it is an active enzyme or a structural protein. The folding process of the polypeptide chain, guided by interactions between amino acid side chains, leads to the formation of secondary, tertiary, and sometimes quaternary structures. These structures work together to stabilize the native conformation of the protein. In some cases, chaperone proteins are required to assist in the correct folding of certain proteins. When a protein undergoes denaturation, its structure unfolds and becomes disorganized, but this does not involve the hydrolysis of peptide bonds. Denaturation can be reversible or irreversible. Disease can occur when a normally functioning protein adopts a conformation that is cytotoxic, as seen in Alzheimer's disease and transmissible spongiform encephalopathies like Creutzfeldt-Jakob disease. In these conditions, abnormal chemical processing causes normal proteins to take on a unique conformational state, leading to the formation of neurotoxic assemblies such as β-pleated sheets in Alzheimer's disease or the conversion of normal protein to a pathogenic conformation in transmissible spongiform encephalopathies.
Central to understanding protein structure is the concept of the native conformation (Fig. 2.15), which is the functional, fully folded protein structure (for example, an active enzyme or structural protein). The unique three-dimensional structure of the native conformation is determined by its primary structure, that is, its amino acid sequence. Interactions between the amino acid side chains guide the folding of the polypeptide chain to form secondary, tertiary, and (sometimes) quaternary structures, which cooperate in stabilizing the native conformation of the protein. In addition, a specialized group of proteins named chaperones is required for the proper folding of many species of proteins. Protein denaturation results in the unfolding and disorganization of the protein’s structure, which are not accompanied by hydrolysis of peptide bonds. Denaturation may be reversible or, more commonly, irreversible. Disease can occur when an apparently normal protein assumes a conformation that is cytotoxic, as in the case of Alzheimer disease (AD) and the transmissible spongiform encephalopathies (TSE), including Creutzfeldt-Jakob disease. In AD, normal proteins, after abnormal chemical processing, take on a unique conformational state that leads to the formation of neurotoxic amyloid β peptide (Aβ) assemblies consisting of β-pleated sheets. In TSE, the infective agent is an altered version of a normal prion protein that acts as a template for converting normal protein to the pathogenic conformation.
Choose the ONE best answer.
.1. Which one of the following statements concerning protein structure is correct?
A. Proteins consisting of one polypeptide have quaternary structure that is stabilized by covalent bonds.
B. The peptide bonds that link amino acids in a protein most commonly occur in the cis configuration.
C. The formation of a disulfide bond in a protein requires the participating cysteine residues to be adjacent in the primary structure.
D. The denaturation of proteins leads to irreversible loss of secondary structural elements such as the α-helix.
E. The primary driving force for protein folding is the hydrophobic effect.
Correct answer = E. The hydrophobic effect, or the tendency of nonpolar entities to associate in a polar environment, is the primary driving force of protein folding. Quaternary structure requires more than one polypeptide, and, when present, it is stabilized primarily by noncovalent bonds. The peptide bond is almost always trans. The two cysteine residues participating in disulfide bond formation may be a great distance apart in the amino acid sequence of a polypeptide (or on two separate polypeptides) but are brought into close proximity by the three-dimensional folding of the polypeptide. Denaturation may be reversible or irreversible.
.2. A particular point mutation results in disruption of the α-helical structure in a segment of the mutant protein. The most likely change in the primary structure of the mutant protein is:
A. glutamate to aspartate.
B. lysine to arginine.
C. methionine to proline.
D. valine to alanine.
Correct answer = C. Proline, because of its secondary amino group, is incompatible with an α-helix. Glutamate, aspartate, lysine, and arginine are charged amino acids, and valine is a branched amino acid. Charged and branched (bulky) amino acids may disrupt an α-helix. [Note: The flexibility of glycine’s R group can also disrupt an α-helix.] .3. In comparing the α-helix to the β-sheet, which statement is correct only for the β-sheet?
A. Extensive hydrogen bonds between the carbonyl oxygen (C=O) and the amide hydrogen (N−H) of the peptide bond are formed.
B. It may be found in typical globular proteins.
C. It is stabilized by interchain hydrogen bonds.
D. It is an example of secondary structure.
E. It may be found in supersecondary structures.