Monday, February 15, 2010

A question about scaffolds

There are two bits of signal transduction dogma that have started to bother me. I don't know why I didn't spot this before.

Kinases are proteins that activate other proteins by attaching phosphate groups to them. Kinase cascades (several kinases in a row) are fairly common in all kinds of signaling pathways. Their main benefits are amplifying and diversifying the signal. Since a kinase is after all an enzyme, it can catalyze the same reaction over and over; it can activate many copies of the next kinase in the cascade, each of which can activate many copies of... and so on into exponential growth. That's how you get amplification, turning a tiny-but-important input into a massive cell-wide response. Diversification comes in when a kinase has more than one target. This comes in handy when the cell needs to respond to one signal by doing several different things all at once.

Scaffolds are large structural proteins that grab several other proteins from a signaling (or metabolic) pathway and hold them together. This helps them get their job done more efficiently. They help make pathways specific. If Enzyme 2 is stuck on a scaffold between Enzyme 1 and Enzyme 3, it can't very well run off to some other part of the cell and mess something up.

So, I perceive a slight conflict here. On one hand, it's helpful to diversify a signal; on the other hand, signals ought to be specific. On one hand, enzyme cascades amplify signals by working catalytically instead of stoichiometrically; on the other hand, when kinases are bound to a scaffold, their stoichiometric ratio is locked at one-to-one. What's going on here?

The obvious answer is that each type of signal processing is used where it's appropriate, and all types are appropriate in different contexts. If this is the explanation, then you would never expect to find a kinase cascade associated with a scaffold. But that's exactly what the MAP kinase cascade does! What gives? I thought the whole point of having a kinase cascade was to amplify and diversify the signal, which is exactly what the scaffold seems to be preventing.

Figure 1: MAP kinase cascade shamelessly associating with scaffold protein. Have they no shame? What has the yeast mating pathway courting ritual come to these days? [Source]

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