Biological Chemistry - Berezov, T. T., & Korovkin, B. F. 1998

Protein Chemistry
Structural Organization of Proteins
Quaternary Structure of Proteins

Quaternary Structure refers to the spatial arrangement of individual polypeptide chains—possessing identical or different primary, secondary, or tertiary structures—into a unified macromolecular entity that is structurally and functionally integrated. Many functional Proteins consist of multiple polypeptide chains held together not by primary covalent bonds, but by non-covalent interactions (similar to those that stabilize tertiary structure). Each individual polypeptide chain, known as a protomer, monomer, or subunit, typically lacks biological activity on its own. A protein acquires this capability only when its constituent protomers assemble in a specific spatial configuration, thereby giving rise to a novel property absent in the monomeric protein. The resulting molecule is conventionally called an oligomer (or multimer). Oligomeric Proteins are most frequently built from an even number of protomers (ranging from 2 to 4, less commonly 6 to 8) with molecular weights spanning from several thousand to hundreds of thousands. Specifically, the Hemoglobin molecule is composed of two identical α- and two β-polypeptide chains, making it a tetramer. The structure of the hemoglobin molecule is illustrated in Fig. 1.23, while Fig. 1.24 clearly shows that it contains four polypeptide chains, each enclosing a heme group—the pigment that gives Blood its characteristic red color (see Chapter 2).

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Fig. 1.23. Oligomeric hemoglobin molecule (red disks represent heme groups).

Under certain conditions (such as the presence of salts, 8 M urea, or drastic pH changes), the hemoglobin molecule reversibly dissociates into two α- and two β-chains. This dissociation is driven by the disruption of Hydrogen Bonds. Removing the salts or urea prompts the spontaneous reassociation of the original hemoglobin molecule (Fig. 1.25).

Fig. 1.24. Model of hemoglobin (after Perutz).

α-Chains are light; β-chains are dark; heme groups are red.

Fig. 1.25. Reversible dissociation of the hemoglobin molecule.

A classic example of an oligomeric molecule, or supramolecular structure, is the tobacco mosaic virus, which is a giant molecule with a Molecular Weight of approximately 40 ∙ 10⁶. It consists of a single RNA molecule (see Chapter 3) and 2,130 protein subunits, each with a mass of 17,500. The virus is roughly 300 nm long and about 17 nm wide. The viral RNA has a helical conformation, around which protein units are threaded, forming a giant supramolecular helical structure comprising about 130 turns (Fig. 1.26). A remarkable feature of this virus is that when the Cell/22.html">RNA and Protein subunits are dissociated by appropriate Methods (such as The addition of detergent) and subsequently remixed (after prior detergent removal), The quaternary structure completely regenerates, fully restoring all physical parameters and biological Functions (including infectivity). Such precision in spontaneous self-assembly is most likely ensured by the information encoded in the Introduction/19.html">Primary Structure of both the RNA molecule and the protein subunits. Thus, the Amino Acid Sequence contains information that is expressed at all Levels of Protein structural Organization.

Many Enzymes also possess a quaternary structure. For instance, phosphorylase a consists of two identical subunits, each containing two peptide chains, making the entire phosphorylase a molecule a tetramer. Individual subunits generally lack catalytic activity; in fact, regulatory enzymes (see Chapter 4) feature an oligomeric quaternary structure. Their function is to maintain the required reaction rates within The Cell.

Fig. 1.26. Self-assembly of the tobacco mosaic virus.

The best-characterized oligomeric enzyme is Lactate dehydrogenase (which catalyzes the reversible conversion of pyruvic acid to lactic acid). It contains Two Types of polypeptide chains—the H type (from Heart) and the M type (from Muscle)—and consists of 4 subunits. Through various combinations of these subunits, the enzyme can exist in 5 different forms. Such enzymes are termed Isoenzymes or, According to the modern Classification, multiple enzyme forms (see Chapter 4).

To date, a subunit structure has been discovered in several hundred proteins. However, the quaternary structure has been elucidated via X-ray crystallography for only a few of them, including hemoglobin*. The primary Forces Stabilizing the quaternary structure are non-covalent interactions between the Contact surfaces of protomers, which interact based on complementarity—a universal principle inherent to living nature. Following its synthesis on the ribosome, a Protein Structure may undergo partial modification (post-translational Processing), such as during The conversion of precursors of certain enzymes or Hormones (e.g., Insulin).

Thus, there is every reason to uphold the concept that proteins possess four LEVELS OF STRUCTURAL organization. Furthermore, each individual protein is characterized by a unique structure that dictates its unique function. Elucidating the structures of diverse proteins therefore serves as a key to understanding The Nature of living systems and, consequently, The Essence of life itself. This path of scientific inquiry may also resolve many Problems associated with human Hereditary diseases, which are rooted in defects of protein Structure and Biosynthesis.

Some researchers are inclined to consider—not without good reason—the existence of a fifth level of protein structural organization. This refers to polyfunctional macromolecular complexes, or associates of different enzymes known as metabolic oligomers or metabolons, which catalyze an entire pathway of substrate transformations (such as higher fatty acid synthetases, the Pyruvate dehydrogenase complex, and the Respiratory Chain).

* The quaternary structure has also been established for A number of IMMUNOGLOBULINS, which consist of light and heavy polypeptide chains linked by Disulfide Bonds, unlike other oligomeric proteins.