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INTRODUCTION

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OBJECTIVES

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.

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BIOMEDICAL IMPORTANCE

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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 posttranslational 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”). Examples of the latter include scurvy (ascorbic acid) and Menkes syndrome (Cu). Next generation therapeutics for hepatitis C and other viral diseases seek to block the maturation of virally encoded proteins by inhibiting the activity of the cyclophilins, a family of peptidylprotein cis-trans isomerases.

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CONFORMATION VERSUS CONFIGURATION

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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 with retention of configuration, generally via rotation about single bonds.

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PROTEINS WERE INITIALLY CLASSIFIED BY THEIR GROSS CHARACTERISTICS

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Scientists initially approached the elucidation of 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 three. Most enzymes ...

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