Protein Quaternary Structures Range from Simple Dimers to Large Complexes

^ Protein Architecture—Quaternary Structure Many proteins have multiple polypeptide subunits. The association of polypeptide chains can serve a variety of functions. Many multisubunit proteins have regulatory roles; the binding of small molecules may affect the interaction between subunits, causing large changes in the protein's activity in response to small changes in the concentration of substrate or regulatory molecules (Chapter 6). In other cases, separate subunits can take on separate but related functions, such as catalysis and regulation. Some associations, such as the fibrous proteins considered earlier in this chapter and the coat proteins of viruses, serve primarily structural roles. Some very large protein assemblies are the site of complex, multistep reactions. One example is the ribosome, site of protein synthesis, which incorporates dozens of protein sub-units along with a number of RNA molecules.

A multisubunit protein is also referred to as a multimer. Multimeric proteins can have from two to hundreds of subunits. A multimer with just a few subunits is often called an oligomer. If a multimer is composed of a number of nonidentical subunits, the overall structure of the protein can be asymmetric and quite complicated. However, most multimers have identical sub-units or repeating groups of nonidentical subunits, usually in symmetric arrangements. As noted in Chapter 3, the repeating structural unit in such a multimeric protein, whether it is a single subunit or a group of sub-units, is called a protomer.

The first oligomeric protein for which the three-dimensional structure was determined was hemoglobin (Mr 64,500), which contains four polypeptide chains and four heme prosthetic groups, in which the iron atoms are in the ferrous (Fe2+) state (Fig. 4-17). The protein portion, called globin, consists of two a chains (141 residues each) and two 3 chains (146 residues each). Note that in this case a and 3 do not refer to secondary structures. Because hemoglobin is four times as large as myoglobin, much more time and effort were required to solve its three-dimensional structure by x-ray analysis, finally achieved by Max Perutz, John Kendrew, and their colleagues in 1959. The subunits of hemoglobin are arranged in symmetric pairs (Fig. 4-23), each pair having one a and one 3 subunit. Hemoglobin can therefore be described either as a tetramer or as a dimer of a3 protomers.

Identical subunits of multimeric proteins are generally arranged in one or a limited set of symmetric patterns. A description of the structure of these proteins requires an understanding of conventions used to define symmetries. Oligomers can have either rotational symmetry or helical symmetry; that is, individual subunits can be superimposed on others (brought to coincidence) by rotation about one or more rotational axes, or by a helical rotation. In proteins with rotational symmetry, the subunits pack about the rotational axes to form closed structures. Proteins with helical symme-

Max Perutz And John Kendrew
Max Perutz, 1914-2002 (left) John Kendrew, 191 7-1997 (right)
Space Filling Model Hemoglobin

FIGURE 4-23 Quaternary structure of deoxyhemoglobin. (PDB ID 2HHB) X-ray diffraction analysis of deoxyhemoglobin (hemoglobin without oxygen molecules bound to the heme groups) shows how the four polypeptide subunits are packed together. (a) A ribbon representation. (b) A space-filling model. The a subunits are shown in gray and light blue; the fi subunits in pink and dark blue. Note that the heme groups (red) are relatively far apart.

Twofold

Threefold

FIGURE 4-23 Quaternary structure of deoxyhemoglobin. (PDB ID 2HHB) X-ray diffraction analysis of deoxyhemoglobin (hemoglobin without oxygen molecules bound to the heme groups) shows how the four polypeptide subunits are packed together. (a) A ribbon representation. (b) A space-filling model. The a subunits are shown in gray and light blue; the fi subunits in pink and dark blue. Note that the heme groups (red) are relatively far apart.

try tend to form structures that are more open-ended, with subunits added in a spiralling array.

There are several forms of rotational symmetry. The simplest is cyclic symmetry, involving rotation about a single axis (Fig. 4-24a). If subunits can be superimposed by rotation about a single axis, the protein has a symmetry defined by convention as Cn (C for cyclic, n for the number of subunits related by the axis). The axis itself is described as an n-fold rotational axis. The afi protomers of hemoglobin (Fig. 4-23) are related by C2 symmetry. A somewhat more complicated rotational symmetry is dihedral symmetry, in which a twofold rotational axis intersects an n-fold axis at right angles. The symmetry is defined as Dn (Fig. 4-24b). A protein with dihedral symmetry has 2n protomers.

Proteins with cyclic or dihedral symmetry are particularly common. More complex rotational symmetries are possible, but only a few are regularly encountered. One example is icosahedral symmetry. An icosahe-dron is a regular 12-cornered polyhedron having 20 equilateral triangular faces (Fig. 4-24c). Each face can

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