3.3 Binding domains in intracellular signalling proteins
The study of intracellular signalling pathways has highlighted the importance of multidomain architecture in protein function and some of the best-characterised binding/regulatory domains are those of signalling proteins.
Signalling pathways serve to communicate extracellular signals, usually recognised and transduced by specific membrane proteins, to effector proteins inside the cell and hence to elicit an appropriate response. Proteins in a signalling pathway are therefore required to interact with both upstream and downstream components via their specific binding domains. Many such interactions are regulated by covalent modification of the interacting proteins, usually phosphorylation. The modular nature of such proteins means that a single signalling protein might bind to a number of other mediators and there is increased potential for modulation of signalling.
Table 5 details some of the key binding domains of signalling proteins and the motifs that they recognise.
Table 5 Binding domains in signalling proteins and the motifs that they recognise.
|Domain||Full name||Binds to:|
|SH2||Src homology 2 domain||phosphorylated tyrosine (phosphotyrosine)|
|SH3||Src homology 3 domain||proline-rich motif|
|PTB||phosphotyrosine binding domain||phosphotyrosine|
|PH*||pleckstrin homology domain||phosphorylated inositol phospholipids|
|PDZ||(None; the name derives from three proteins in which the domain was first identified.)||specific (~5-residue) motifs at C-terminus or at the end of β hairpin loops|
Though these binding domains recognise certain motifs, the specific interaction between individual proteins is determined by the special context of the motif within the peptide. PDZ domains are often found in so-called ‘scaffold’ proteins. Typically a scaffold protein has several such domains, each of which recruits a specific protein to the complex.
As well as domains that specify interactions with other proteins, many signalling proteins also contain domains with enzyme activity (e.g. kinases, phosphatases). These enzymatic domains may act on proteins recruited by binding domains, thereby regulating their activity. Enzyme activity in one domain of a protein may also be directed at another domain in the same protein (e.g. autophosphorylation).
In these ways, a complex network of interactions can build up in which there is potential for manipulation of activities and integration of several signalling pathways.