Chapter 24

Protein Domains and Signal

Transduction

Modular structure of proteins

Many proteins share regions of similar architecture called domains. These are discrete, structurally homologous units that may also behave as

functional elements. In previous chapters, we have seen how the domains of signalling proteins can be crucial for their function. We now consider the origin of structural domains and how they have been acquired by proteins throughout evolution, leading to functional diversification. To illustrate how the acquisition or modification of function by domains affects signalling mechanisms, we go on to discuss in more detail a few selected domains that are important in signalling.

Structural domains

The term domain was initially used to describe different spatially organized segments of a protein. These might be defined simply by location. For

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Signal Transduction

instance, a transmembrane protein will possess distinct intracellular, extracellular, and transmembrane domains. Alternatively, different regions may have different functions, as in enzymes that have separate catalytic and regulatory domains. Furthermore, similar enzymes may possess corresponding domains that exhibit homologies of sequence and structure.

A wider examination of protein structures reveals a pattern of modularity which extends these notions. That is, there are common, compact structural units which recur in different proteins or which may be repeated within a single polypeptide. These units consist typically of stretches of 40–100 amino acids that fold independently of the main chain as globular, closed structures with a hydrophobic core. These regions are characterized by their structural homology and they are very widespread. Most proteins contain at least

two structural domains and many signalling molecules have more. Proteins composed of multiple domains have been termed mosaic proteins. The range of 3-dimensional structures that domains adopt seems to be restricted to a small proportion of the theoretically possible folds.

The evolution and shuffling of domains

Some types of domain occur in both archaea and bacteria as well as in eukaryotic organisms, and so it is inferred that they were also present in their common ancestor. Other domains are of recent origin, occurring only in eukaryotic organisms. (Indeed, the incidence of structural domains in microbes is much lower than in eukaryotic cells.) Some of the ancestral domains possess essential metabolic enzymatic properties. Others enable important protein–protein interactions. Details of their origin are lacking, but

they may have arisen through the recombination of ancestral short sequences (antecedent domain sequences) to form stable core assemblies. Those with functional importance then persisted.1

The commonest mechanism by which biological complexity has developed is through gene duplication. Initially, duplication might generate more mRNA, but it can lead to a change of function. Gene duplication may also be partial (internal duplication), causing a gene to become elongated. An outcome is the repetition of all, or part, of a domain sequence within a protein, and if one of the repeated domains goes on to gather mutations, it may acquire a new function. Another process by which a new domain can be acquired is by the insertion of a sequence from one gene into another by recombination. The N- and C-termini of domains introduced in this way are usually adjacent, so that insertion into the polypeptide chain causes minimal disruption of the fold of the recipient protein. By the same principle, the linear sequence of a structural domain may itself be interrupted by another ‘nested’ domain. Such insertions occur most readily at loops in the parent structure. For example, the

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