Multidomain Proteins

Abstract

Protein domains that have a necessary function are often used in many different proteins. Protein architecture has evolved to utilise a large set of such domains in forming the thousands of different proteins necessary for any living organism. Definitions for domains are still somewhat variable, and therefore current databases show domain sizes ranging from a few amino acids to more than 800 amino acids, with the great majority at 50–150 amino acids, or approximately 5–16 kDa. Simple proteins normally contain only one or two domains, whereas larger proteins may have incorporated more than 30 domains needed for the more complex cellular functions. At least two‐thirds of mammalian proteins have more than one domain. Only multicellular eukaryotes have a significant proportion of proteins with repeating domains.

Key Concepts:

  • Protein domains may represent the earliest or simplest proteins formed at the beginning of life.

  • Protein domains are usually the individual units for protein folding.

  • Protein domains often serve as structural units that define a protein.

  • By having useful functions that may be selected, protein domains become central units in the evolution of diverse proteins.

  • Almost all protein domains have a specific ligand‐binding function.

  • Conformational changes in a protein may involve a reorientation of two or more domains to form or disrupt a ligand‐binding site, and thereby control an enzyme's catalytic activity.

Keywords: protein structure; domain; module; evolution; protein databases

Figure 1.

The sizes of protein structures. Protein subunits are usually 10 kDa or larger. Modules have sizes below 80 amino acids. Domains vary more in size, depending on how they are defined. A size scale permits comparison for both the number of amino acids in a protein and its size in kDa. Simple enzymes have only a single type of catalytic activity, and are not subject to sophisticated regulatory controls. Complex enzymes are always larger, and may contain two or more catalytic centres, and frequently have additional binding sites for one or more regulatory effectors.

Figure 2.

Sizes of protein domains. As these sizes are most commonly determined from the protein sequence, they are defined by the number of amino acids contained in any domain, as shown on the abscissa. A comparison scale in kDa is shown along the top of the figure. Reproduced from v3.5 of the CATH protein domain website (Sillitoe et al., ).

Figure 3.

Sizes of human proteins.

Figure 4.

A model for the evolution of new proteins. Modules, at an average size of 50 amino acids, are coded by exons, and are large enough to have tertiary structure. Domains, at an average size of 150 amino acids, are formed by two or more modules. Simple enzymes generally are formed by one domain. Gene duplication leads to copies for some enzymes, which become altered by mutation and selection if a new or better activity evolves. Fusion of two or more genes leads to multidomain proteins with multiple activities.

Figure 5.

Examples of proteins with various assortments of modules or domains. Domains or modules are identified and their size in amino acids is in parentheses. A number following a domain element denotes the frequency of repetition for that domain. SH, Sarc homology; THSP, thrombospondin and VWA, von Willebrand factor, type A.

Figure 6.

A model for the structure of porcine fatty acid synthase. Each subunit of the protein dimer contains the separate protein domains: ACP, acyl carrier protein; DH, dehydratase; ER, enoyl reductase; KR, β‐keto reductase; KS, β‐ketoacyl synthetase, LD: linker domain; MAT, malonyl acetyltransferase; ψME, pseudomethyltransferase and TE: thioesterase. (a) Schematic representation of the crystal structure. (b) Linear sequence of the domains in the protein. Adapted from Maier et al. ().

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Further Reading

Bennett WS and Huber R (1984) Structural and functional aspects of domain motions in proteins. Critical Reviews in Biochemistry 15: 290–384.

Corpet F, Servant F, Gouzy J and Kahn D (2000) ProDom and ProDom‐CG: tools for protein domain analysis and whole genome comparisons. Nucleic Acids Research 28: 267–269.

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Traut TW (1988) Do exons code for structural or functional units in proteins? Proceedings of the National Academy of Sciences of the USA 85: 2944–2948.

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Traut, Thomas(May 2014) Multidomain Proteins. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005053.pub2]