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Protein Quaternary Secondary article Structure: Subunit–Subunit Article Contents . Introduction Interactions . Quaternary Structure Assembly . Folding and Function Susan Jones, University College, London, England . Protein–Protein Recognition Sites . Concluding Remarks Janet M Thornton, University College, London, England The quaternary structure of proteins is the highest level of structural organization observed in these macromolecules. The multimeric proteins that result from quaternary structure formation involve the association of protein subunits through hydrophobic and electrostatic interactions. Protein quaternary structure has important implications for protein folding and function. Introduction from, other components. Using these definitions, the Proteins are organized into a structural hierarchy. The haemoglobin tetramer (comprised of two a and two b polypeptide chain at the primary structural level comprises polypeptide chains) is defined as an oligomer consisting of a linear, noncovalently linked amino acid residue se- two protomers, each consisting of two monomers, i.e. one a quence. Secondary structure is the level at which the linear and one b polypeptide chain. The definition of a subunit sequences aggregate to form structural motifs such as allows the term to be used for either the a-orb-monomer, helices and sheets. The tertiary structure is formed by or for the ab-protomer. The term multimer is also widely packing of the secondary structural elements into one or used in the literature and is defined here as a protein with a more compact globular domains. In many cases proteins finite number of subunits that need not be identical. are composed of only a single polypeptide chain that has The quaternary nature of some proteins was first tertiary structure as its highest level of organization, e.g. identified from centrifugation experiments devised in the lysozyme. These are termed monomeric proteins. How- 1920s to calculate the molecular weights of proteins. Since ever, many proteins are composed of more than one then, combinations of association and hybridization polypeptide chain, associated into assemblies possessing a techniques have led to the discovery of a large number of specific quaternary structure, e.g. dimeric interleukin 8 and proteins possessing quaternary structure. To date, the three-dimensional structures of many hundreds of multi- tetrameric a2b2 human haemoglobin (Figure 1). The most complex assemblies are those observed in the higher order meric proteins with identical subunits (oligomers) and structures, such as the icosahedral viruses, that comprise 60 nonidentical subunits have been solved by X-ray crystal- monomers in identical symmetrical positions. The qua- lography. An example of an oligomeric protein solved by ternary structure of a protein describes the stoichiometry this method is aspartyl protease from human immunode- and stereochemistry of assemblies of noncovalently linked ficiency virus 1 (HIV-1) retrovirus (Navia et al., 1989). This subunits, characterized by the lower levels of structural protein functions to release structural proteins and organization (Jaenicke, 1987). enzymes (such as reverse transcriptase and integrase) from In a discussion of protein quaternary structure it is viral polyprotein products. HIV-1 protease is a homo- important to adhere to a single set of definitions. Those dimer, in which each subunit comprises almost exclusively widely used in the literature, and adopted here, were b sheet, turn and extended polypeptide structural elements derived by Monod et al. (1965) in their theoretical model of (Figure 1). Each subunit contributes one highly conserved allosteric effects in protein structures. An oligomer is Asp-Thr-Gly catalytic triad sequence to form a symmetric defined as a protein assembly containing a finite, relatively active site in the dimer. An example of a multimeric protein small number of identical subunits. Protomers are defined with nonidentical subunits solved by X-ray crystallogra- as the identical subunits associated within an oligomeric phy is the glycoprotein hormone, human chorionic protein. A monomer is defined as the fully dissociated gonadotrophin (Lapthorn et al., 1994). This protein is protomer, or any protein that is not made up of subunits. A secreted by the placenta in the early weeks of pregnancy subunit is purposely undefined, and may be used to refer to and stimulates the secretion of the steroid progesterone. any chemically or physically identifiable submolecular The protein is an ab-heterodimer in which each subunit has entity within a protein, whether identical to or different a similar extended topology that includes a cysteine knot motif, common to a number of growth factors. The a and b ENCYCLOPEDIA OF LIFE SCIENCES © 2001, John Wiley & Sons, Ltd. www.els.net 1 Protein Quaternary Structure: Subunit–Subunit Interactions Figure 1 Molscript diagrams depicting the secondary structure elements and the quaternary structure of (a) homodimeric interleukin 8; (b) heterodimeric human chorionic gonadotrophin; (c) homodimeric HIV-1 protease; (d) heterotetrameric human haemoglobin. In each diagram the protein subunits are differentiated by colour, and in (d) one ab-protomer of haemoglobin is coloured red and one green. The haem groups in each subunit shown in (d) are depicted by ball-and-stick representations. subunits are integrally associated with a segment of the b protomer), and domain of bonding (the two, linked subunit wrapped around the a subunit and covalently binding sets) (Monod et al., 1965). In heterologous linked by a disulfide bond (Figure 1). associations the domain of bonding is made up of two different binding sets, and in isologous associations the two binding sets involved are identical (Figure 2). In pseudoi- sologous associations, the domain of bonding comprises Quaternary Structure Assembly two almost identical binding sets. In isologous associations the binding set of each protomer is ‘covered’ by the Protein stoichiometry equivalent binding set on the other protomer, hence these associations tend to lead to finite closed structures. The stoichiometry of proteins possessing a quaternary structure considers the number of subunits involved in the assemblies. The association of subunits in quaternary structure can lead to the formation of closed structures, of ab b ababa which dimers and tetramers are by far the most frequently observed. In addition, quaternary proteins can exhibit open elongated polymer structures. The way in which ba d cdcdc different numbers of protein subunits associate to form aggregates has been defined as macroassociation. (a) (b) The process of macroassociation is divided into three Figure 2 Modes of association in multimeric proteins: (a) isologous, in modes, namely heterologous, isologous and pseudoisolo- which the binding sets (indicated by the letters ‘a’ and ‘b’) are identical; (b) gous. Each can be defined using two terms: binding set (the heterologous, in which the binding sets (indicated by the letters ‘a’, ‘b’, ‘c’ residues of one protomer involved in binding to one other and ‘d’) are not identical. Adapted from Monod et al., 1965. 2 Protein Quaternary Structure: Subunit–Subunit Interactions Heterologous associations can involve multiple binding the association itself may be symmetrical but minor sets on a single protomer that can lead to infinite open structural changes between the subunits may exist. Such structures. If an oligomer has an odd number of equivalent changes generally only exist in the crystal form of the protomers, then the associations between them must be protein, where identical, symmetrically related subunits heterologous; however, if an oligomer has an even number might be in an anisotropic crystal environment. of equivalent protomers, the associations can be either The symmetry of an oligomeric protein affects its isologous, heterologous or a mixture of the two. Some properties and functions, and can be crystallographic or elongated proteins, such as actin, are formed by indefinite noncrystallographic. The unit cell of a crystal is the basic heterologous association of globular protomers; however, building block, repeated infinitely by translation in three heterologous associations can also lead to closed struc- dimensions. The asymmetric unit is the basic repeating tures, such as those observed in the trimeric bacteriochlor- unit, which is related to all the other identical units in the ophyll protein and the tetrameric manganese superoxide unit cell by the operation of the symmetry elements. If the dismutase. volume of the asymmetric unit of a crystal accommodates The definition of different modes of association raised just one subunit of an oligomeric protein, then the other the question of which one is most prevalent amongst subunit(s) will be related to it by the same symmetry proteins. Monod et al. (1965) proposed that the exclusive operation(s) that relate the asymmetric units to each other. use of isologous associations would lead only to dimers and In this case the symmetry of the oligomer is expressed in the tetramers. In support of this is the prevalence of dimers and crystallographic symmetry. Alternatively, the asymmetric tetramers amongst the proteins solved, and by implication unit of the crystal may accommodate the whole oligomer isologous associations. However, thermodynamic calcula- or more than one oligomer. In this case the symmetry of the tions on the possibilities of all-isologous, all-heterologous protein will not be determined by the crystallographic
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