The term “tertiary structure” refers to the entire three-dimensional conformation of an individual polypeptide. It indicates, in three-dimensional space, how secondary structural features—helices, sheets, bends, turns, and loops—assemble to form domains and how these domains relate spatially to one another. A domain is a section of the protein structure sufficient to perform a particular chemical or physical task such as binding of a substrate or other ligand. Most domains are modular in nature, that is, contiguous in both primary sequence and three-dimensional space (Figure1). Simple proteins, particularly those that interact with a single substrate or other ligand, such as lysozyme, triose phosphate isomerase (see Figure 2), or the oxygen storage protein myoglobin, often consist of a single domain. By contrast, lactate dehydrogenase is comprised of two domains, an N-terminal NAD+-binding domain and a C-terminal binding domain for the second substrate, pyruvate (see Figure 1). Lactate dehydrogenase is one of the family of oxidoreductases that share a common N-terminal NAD(P)+-binding domain known as the Rossmann fold. By fusing a segment of DNA coding for a Rossmann fold domain to that coding for a variety of C-terminal domains, a large family of oxidoreductases have evolved that utilize NAD(P)+/NAD(P)H for the oxidation and reduction of a wide range of metabolites. Examples include alcohol dehydrogenase, glyceraldehyde-3-phosphate dehydrogenase, malate dehydrogenase, quinone oxidoreductase, 6-phosphogluconate dehydrogenase, d-glycerate dehydrogenase, and formate dehydrogenase.

Fig1. Polypeptides containing two domains. Left: Shown is the three-dimensional structure of a monomer unit of the tetrameric enzyme lactate dehydrogenase with the substrates NADH (red) and pyruvate (blue) bound. Not all bonds in NADH are shown. The color of the polypeptide chain is graded along the visible spectrum from blue (N-terminal) to orange (C-terminal). Note how the N-terminal portion of the polypeptide forms a contiguous domain, encompassing the upper portion of the enzyme, responsible for binding NADH. Similarly, the C-terminal portion forms a contiguous domain responsible for binding pyruvate. Right: Shown is the three-dimensional structure of the catalytic subunit of the cAMP-dependent protein kinase with the substrate analogs ADP (red) and peptide (purple ribbon) bound. The color of the polypeptide chain is graded along the visible spectrum from blue (N-terminal) to orange (C-terminal). Protein kinases transfer the γ-phosphoryl group of ATP to protein and peptide substrates. Note how the N-terminal portion of the polypeptide forms a contiguous domain rich in β sheet that binds ADP. Similarly, the C-terminal portion forms a contiguous, α–helix–rich domain responsible for binding the peptide substrate. (Left, Adapted with permission from Protein Data Bank ID no. 3ldh; Right, Adapted with permission from Protein Data Bank ID no. 1jbp.)

Fig2. Examples of the tertiary structure of proteins. Left: The enzyme triose phosphate isomerase complexed with the substrate analog 2-phosphoglycerate (red). Note the elegant and symmetrical arrangement of alternating β sheets (gray) and α helices (green), with the β sheets forming a β-barrel core surrounded by the helices. (Adapted from Protein Data Bank ID no. 1o5x.) Right: Lysozyme complexed with the substrate analog penta-N-acetyl chitopentaose (red). The color of the polypeptide chain is graded along the visible spectrum from purple (N-terminal) to tan (C-terminal). Note, the concave shape of the domain forms a binding pocket for the pentasaccharide, the lack of β sheet, and the high proportion of loops and bends. (Adapted with permission from Protein Data Bank ID no. 1sfb.)

Not all domains bind substrates. Hydrophobic domains anchor proteins to membranes or enable them to span membranes. Localization sequences target proteins to specific subcellular or extracellular locations such as the nucleus, mitochondria, secretory vesicles, etc. Regulatory domains trigger changes in protein function in response to the binding of allosteric effectors or covalent modifications. Combining the genetic material coding for individual domain modules provides a facile route for generating proteins of great structural complexity and functional sophistication (Figure 3).

Fig3. Some multidomain proteins. The rectangles represent the polypeptide sequences of a forkhead transcription factor; 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, a bifunctional enzyme whose activities are controlled in a reciprocal fashion by allosteric effectors and covalent modification; phenylalanine hydroxylase, whose activity is stimulated by phosphorylation of its regulatory domain; and a receptor for atrial natriuretic peptide receptor, whose intracellular domain transmits signals through protein–protein interactions with heterotrimeric GTP-binding proteins. Regulatory domains are colored orange, catalytic domains in blue or purple, protein–protein interaction domains (Pr-Pr) in green, DNA-binding domains in gray, nuclear localization sequences in red, ligand-binding domains in light yellow, and transmembrane domains in black. The kinase and bisphosphatase activities of 6-phosphofructo 2-kinase/fructose-2,6-bisphosphatase are catalyzed by the N- (PFK-2) and C-terminal (FBP2-ase) proximate catalytic domains, respectively.

Proteins containing multiple domains can also be assembled through the association of multiple polypeptides, or protomers. Quaternary structure defines the polypeptide composition of a protein and, for an oligomeric protein, the spatial relationships between its protomers or subunits. Monomeric proteins con sist of a single polypeptide chain. Dimeric proteins contain two polypeptide chains. Homodimers contain two copies of the same polypeptide chain, while in a heterodimer the polypeptides differ. Greek letters (α, β, γ, etc.) are used to distinguish different subunits of a hetero-oligomeric protein, and subscripts indicate the number of each subunit type. For example, α4 designates a homotetrameric protein, and α2 β2 γ, a protein with five subunits of three different types.

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