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After studying this chapter, you should be able to:

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  • Describe multiple chromatographic methods commonly employed for the isolation of proteins from biologic materials.
  • Explain how scientists analyze the sequence or structure of a protein to extract insights into its possible physiologic function.
  • List several of the posttranslational alterations that proteins undergo during their lifetime and the influence of such modifications upon a protein's function and fate.
  • Describe the chemical basis of the Edman method for determining primary structure.
  • Give three reasons why mass spectrometry (MS) has largely supplanted chemical methods for the determination of the primary structure of proteins and the detection of posttranslational modifications.
  • Explain why MS can detect posttranslational modifications that are not detected by Edman sequencing or DNA sequencing.
  • Describe how DNA cloning and molecular biology made the determination of the primary structures of proteins much more rapid and efficient.
  • Explain what is meant by “the proteome” and cite examples of its ultimate potential significance.
  • Comment on the contributions of genomics, computer algorithms, and databases to the identification of the open reading frames (ORFs) that encode a given protein.

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Proteins are physically and functionally complex macromolecules that perform multiple critically important roles. For example, an internal protein network, the cytoskeleton (Chapter 49) maintains cellular shape and physical integrity. Actin and myosin filaments form the contractile machinery of muscle (Chapter 49). Hemoglobin transports oxygen (Chapter 6), while circulating antibodies defend against foreign invaders (Chapter 50). Enzymes catalyze reactions that generate energy, synthesize and degrade biomolecules, replicate and transcribe genes, process mRNAs, etc (Chapter 7). Receptors enable cells to sense and respond to hormones and other environmental cues (Chapters 41 and 42). Proteins are subject to physical and functional changes that mirror the life cycle of the organisms in which they reside. A typical protein is “born” at translation (Chapter 37), matures through posttranslational processing events such as selective proteolysis (Chapters 9 and 37), alternates between working and resting states through the intervention of regulatory factors (Chapter 9), ages through oxidation, deamidation, etc (Chapter 52), and “dies” when degraded to its component amino acids (Chapter 29). An important goal of molecular medicine is to identify biomarkers such as proteins and/or modifications to proteins whose presence, absence, or deficiency is associated with specific physiologic states or diseases (Figure 4–1).

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Figure 4-1
Graphic Jump Location

Diagrammatic representation of the life cycle of a hypothetical protein. (1) The life cycle begins with the synthesis on a ribosome of a polypeptide chain, whose primary structure is dictated by an mRNA. (2) As synthesis proceeds, the polypeptide begins to fold into its native conformation (blue). (3) Folding may be accompanied by processing events such as proteolytic cleavage of an N-terminal leader sequence (Met-Asp-Phe-Gln-Val) or the formation ...

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