Protein Domains and Signal Transduction

lipid; some PH domains bind to phosphoinositide headgroups enabling cytosolic proteins to locate to particular membrane sites. Such domains have been termed protein interaction domains.4 The variety is wide, and some illustrative examples are discussed below. A fuller set of descriptions is provided at http://www.mshri.on.ca/pawson/domains.html.

Protein interaction domains are essential cogs in the machinery of most, if not all cellular signalling pathways. At the simplest level, they may allow two separate components to associate just long enough to ensure the

propagation of a downstream signal. Alternatively, they can enable an array of components to assemble into large multimolecular complexes. Importantly, this happens at specific cellular locations determined by interactions of

the components with local proteins and phospholipids. Whether simple or complex, these processes are initiated by the touch of a button, often a single event, such as the binding of a ligand to its receptor.

The inventory of domains

Detection

Since the degree of sequence homology among domains of the same type may be limited, their detection using basic sequence alignment tools (e.g. BLAST) can be difficult, particularly when a nested domain interrupts the sequence of another. A better method is to compare a sequence with a statistical profile calculated from a library of known domain sequences. The probability that the test sequence matches the profile is scored, a high score predicting the presence of the domain. The most effective profiles are hidden Markov models, and a number of the publicly accessible protein databases utilize libraries of these models to predict domain architecture (for example Pfam, SMART, TIGRFAM, PANTHER, PIRSF, Gene3D, and SUPERFAMILY). With successive refinements to these tools, previously unperceived domains

have been revealed in many proteins. However, differences in definitions and analysis methods mean that domain architectures predicted for a given sequence by the different approaches are not always identical.

Classification

Domains may be classified on the basis of their sequence, structural fold, or function. As already discussed, function and fold are not always correlated, nor are fold and ancestry. Where there are clear sequence similarities, domains have been assigned to families, and where there is structural and functional evidence of descent from a common ancestor, families have been grouped in superfamilies (SCOP) or clans (Pfam5). However, because definitions vary, such assignments may differ between databases.

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