Chapter 5

After studying this chapter, you should be able to:

• Indicate the advantages and drawbacks of several approaches to classifying proteins.
• Explain and illustrate the primary, secondary, tertiary, and quaternary structure of proteins.
• Identify the major recognized types of secondary structure and explain supersecondary motifs.
• Describe the kind and relative strengths of the forces that stabilize each order of protein structure.
• Describe the information summarized by a Ramachandran plot.
• Indicate the present state of knowledge concerning the stepwise process by which proteins are thought to attain their native conformation.
• Identify the physiologic roles in protein maturation of chaperones, protein disulfide isomerase, and peptidylproline cis–trans-isomerase.
• Describe the principal biophysical techniques used to study tertiary and quaternary structure of proteins.
• Explain how genetic and nutritional disorders of collagen maturation illustrate the close linkage between protein structure and function.
• For the prion diseases, outline the overall events in their molecular pathology and name the life forms each affects.

In nature, form follows function. In order for a newly synthesized polypeptide to mature into a biologically functional protein capable of catalyzing a metabolic reaction, powering cellular motion, or forming the macromolecular rods and cables that provide structural integrity to hair, bones, tendons, and teeth, it must fold into a specific three-dimensional arrangement, or conformation. In addition, during maturation post-translational modifications may add new chemical groups or remove transiently-needed peptide segments. Genetic or nutritional deficiencies that impede protein maturation are deleterious to health. Examples of the former include Creutzfeldt–Jakob disease, scrapie, Alzheimer's disease, and bovine spongiform encephalopathy (“mad cow disease”). Scurvy represents a nutritional deficiency that impairs protein maturation.

The terms configuration and conformation are often confused. Configuration refers to the geometric relationship between a given set of atoms, for example, those that distinguish L- from D-amino acids. Interconversion of configurational alternatives requires breaking (and reforming) covalent bonds. Conformation refers to the spatial relationship of every atom in a molecule. Interconversion between conformers occurs without covalent bond rupture, with retention of configuration, and typically via rotation about single bonds.

Scientists initially approached structure–function relationships in proteins by separating them into classes based upon properties such as solubility, shape, or the presence of nonprotein groups. For example, the proteins that can be extracted from cells using aqueous solutions of physiologic pH and ionic strength are classified as soluble. Extraction of integral membrane proteins requires dissolution of the membrane with detergents. Globular proteins are compact, roughly spherical molecules that have axial ratios (the ratio of their shortest to longest dimensions) of not over 3. Most enzymes are globular proteins. By contrast, many structural proteins adopt highly extended conformations. These fibrous proteins possess axial ratios of 10 or more.

Lipoproteins and glycoproteins contain covalently bound lipid and carbohydrate, respectively. Myoglobin, hemoglobin, cytochromes, and many other metalloproteins contain tightly associated metal ions. While more precise classification schemes have emerged based upon similarity, or homology, in amino acid sequence and ...

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