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C H A P T E R 6

PROTEIN ARCHITECTURE: RELATIONSHIP OF

FORM AND FUNCTION

Jia-huai Wang and Michael J. Eck

Previous chapters have outlined the central dogma of molecular hydrophobic amino acids predominate in the interior of proteins,
biology: the storage of genetic information in DNA and its regulated where they are sequestered from water. They tend to pack against
transcription into messenger RNA and eventual translation into each other via van der Waals interactions, which contribute to the
proteins. In this chapter, we briefly outline the chemical structure of overall stability of folded protein domains. By contrast, hydrophilic,
proteins and their posttranslational modifications. We explain how or polar, amino acids (including serine, threonine, tyrosine, aspara-
the properties of the 20 amino acids of which proteins are composed gine, glutamine, cysteine, and tryptophan) are often exposed on the
allow these polymers to fold into compact, functional domains and surface of proteins, where they can form hydrogen bonds with each
how particular domains and motifs have been assembled, modified, other, with the protein main chain, and with water or ligand mol-
and reused in the course of evolution. Finally we describe a sampling ecules. Hydrogen bonding refers to the attractive interaction of a
of proteins and domains of relevance to the hematologist and explore proton covalently bonded to one electronegative atom (usually a
briefly how point mutations, chromosomal translocations, and other nitrogen or oxygen in proteins) with another electronegative atom.
genetic alterations may modify protein structure and function to Hydrogen bonds are an important contributor to the stability of
cause disease. proteins and to the specificity of protein–protein and protein–ligand
interactions. Charged amino acids are also polar and are important
participants in hydrogen bonding. Hydrogen bonds between nega-
AMINO ACIDS AND THE PEPTIDE BOND tively charged (acidic) and positively charged (basic) amino acids,
also termed salt bridges, are also important components of protein
Proteins are linear polymers of the 20 naturally occurring amino stability and protein–protein interactions. The acidic amino acids
acids, linked together by the peptide bond. All of the amino acids are aspartate and glutamate, and the basic amino acids are lysine,
share a common core or backbone structure and differ only in the arginine, and histidine. Histidine merits special mention, as it is the
“side chain” emanating from the central “α-carbon” of this core. The only amino acid whose side chain can be protonated or unproton-
common backbone elements include an amino group, the central ated, and therefore charged or uncharged, around physiologic ranges
α-carbon, and a carboxylic acid group. Peptide bonds are formed by of pH. For this reason, histidine is part of many enzyme-active sites.
reaction of the carboxylic acid of one amino acid with the amino For example, in the serine proteases of the coagulation cascade, an
group of the next amino acid in the chain. This reaction is templated active site histidine acts as a general base, accepting and then releas-
and catalyzed by the ribosome and leads to the release of water formed ing a proton in sequential steps of the enzymatic reaction. It is also
by the loss of an –OH group from the carboxylic acid of one amino important to note that some of the polar amino acids are amphipa-
acid residue and a hydrogen atom from the amino group of the next thic; in other words, they have both polar and hydrophobic character.
residue in the chain. Coupling of multiple amino acids together via This dual nature of threonine, lysine, tyrosine, arginine, and trypto-
the peptide bond produces the repeating main-chain structure of the phan makes them well suited for participating in protein–protein
polypeptide chain, composed of the amide (NH) nitrogen, alpha interactions, where they may be alternately exposed to solvent or
carbon (Cα), and carbonyl carbon (CO), followed by the amide buried upon formation of a complex.
nitrogen of the next amino acid in the chain (Fig. 6.1A). The reso-
nant, partial double-bond character of the peptide bond prevents
rotation about this bond; thus the five main-chain carbon, nitrogen, Protein Secondary Structure
and oxygen atoms of each peptide unit lie in a plane. The conforma-
tional flexibility in the polypeptide chain is conferred by rotation The alternating pattern of hydrogen bond–donating amide groups
about the bonds on either side of the α-carbon atom; these bond and hydrogen bond–accepting carbonyl groups gives rise to repeating
angles are referred to as phi and psi angles. The angle of the N–Cα elements of protein structure that are stabilized by hydrogen bonds
bond is the phi angle (Φ), and that of the Cα–CO bond is the psi between these main-chain groups. These secondary structure elements
angle (ψ). include α-helices and β-sheets. In an α-helix, the main chain adopts
The primary structure or primary sequence of a protein refers to a right-handed helical conformation in which the carbonyl oxygen of
th
the order in which various residues of the 20 amino acids are the i residue in the polypeptide chain accepts a hydrogen bond from
th
assembled into the polypeptide chain, and this sequence is critically the amide nitrogen of the (I + 4) residue (see Fig. 6.1B). The pattern
important for determining the three-dimensional fold and thus func- may repeat for only a few residues, forming a single turn of β-helix,
tion of the protein. It is the diverse chemical structure and physico- or for more than 100 residues, forming dozens of turns of helix. There
chemical properties of the 20 amino acid side chains that guide the are 3.6 residues per turn of helix, and the pitch or rise of the helix is
three-dimensional fold of proteins and also provide for the enormous 1.5 Å per residue or 5.4 Å per turn. The side chains of residues in an
repertoire of protein function, from catalysis of myriad chemical α-helix project outward, away from the central axis of the helix.
reactions to immune recognition, to establishment of muscle and Often a polar side chain will “cap” the end of a helix by forming a
skeletal structure. hydrogen bond with the otherwise unpartnered amide or carbonyl
The amino acids can be divided into general classes based on the group at the N- or C-terminal end of the helix.
physicochemical properties of their side chains, and in particular In a β-sheet secondary structure, the protein backbone adopts an
their propensity to interact with water. Hydrophobic amino acids extended conformation and two or more strands are arranged side by
have aliphatic or aromatic side chains and include alanine, valine, side, with hydrogen bonds between the strands. The strands can run
leucine, isoleucine, proline, methionine, and phenylalanine. The in the same direction (parallel β-sheet) or antiparallel to one another.

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