Signal Transduction

Domain function

We have seen how protein function may be enhanced through the acquisition of structural domains and in preceding chapters we have encountered numerous examples of signalling proteins having domains that are key functional elements. We now consider whether domains with similar structures exhibit similar functions. The domain shuffling mechanisms described above, together with mutation, allow function to be acquired, modified or lost over time. Thus domains of common origin may differ in function and, conversely, structurally dissimilar domains may have similar functions (functional convergence). For example, both SH2 domains and PTB domains bind to phosphotyrosine residues, but they are structurally distinct. By contrast, domains with the same fold can exhibit quite different functions. PTB domains and PH domains share the same basic structure, but PH domains bind to phosphoinositides and to G protein -subunits. To complicate matters further, some domains with so-called characteristic functions may,

in some proteins, have lost or never acquired that function, existing simply as structural elements. Thus a particular structural domain in a protein may confer a specific function, but it does not guarantee it.

Catalytic domains

It is not always possible to assign function to a single, spatially distinct region of an enzyme. The residues that form the active sites and that take part in the catalytic process are often from disparate segments of the chain. For

this reason, lysozyme was classed as a single domain protein. In other cases, enzyme activity resides in regions that can operate as independent functional units. For example, trypsin-like serine protease domains are widely distributed (trypsin itself, chymotrypsin, choline esterases, elastase, plasminogen, etc.). They are identifiable by their structure, and their presence can be used

to predict proteolytic activity (although they are not necessarily active). Other domains having catalytic properties include protein kinase domains (serine/threonine kinase and tyrosine kinase domains), protein phosphatase domains, the X and Y catalytic domains of the phospholipases C, and guanine nucleotide exchange factor (GEF) domains, such as RasGEF and RhoGEF.

Protein interaction domains

A large proportion of known structural domains do not possess any inherent enzyme activity, but do provide sites of interaction with other molecules. Such domains can bring about the association of polypeptide chains with each other, or with lipids, nucleic acids, small molecules, or ions. The binding may be quite specific and may generate interor intramolecular interactions. For instance, SH2 domains can recognize and bind phosphotyrosines within specific peptide sequences. Likewise, SH3 domains can bind specifically to proline-rich regions. Alternatively, the binding target may be a membrane

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