Question

Reversible protein phosphorylation is a critical mediator of cellular physiology. What are the roles of phosphorylation with respect to the Tau protein? How does the presence of multiple phosphorylation sites complicate our understanding it’s regulation (or does it?). In term of protein evolution, is this a selective advantage, side effect, or something else entirely?

Answer 1

Tau proteins are found rich in neurons of CNS. They are important protein for maintaining stability of microtubules, especially in axons. Tau is a phosphoprotein and contain around 85 potential serine (S), threonine (T), and tyrosine (Y) phosphorylation sites. Various kinase regulate the phosphorylation of tau proteins. For example, serine-threonine protein kinase N1 (PKN) activates, it phosphorylate the tau protein and results in disassemble of microtubules. Microtubules are dynamic structure which means they asssemble and disassemble in response to various signaling. This is important for cytoskeleton rearrangement, cell motility, cell division and transport of organelles.

Presence of many phosphorylation sites in protein increase complexity and their regulation. Different sites of [proteins could be target of different kinase activated by different signaling pathways. Each signaling pathways and associated proteins could make link(s) with other signaling pathways, thus adding further to complexity and our understanding.

In terms of protein evolution, presence of protein phosphorylation sites indicates functional importances. If phosphorylated sites are conserved, that means, such sites may have important functional roles. Various studies have shown that phosphosites are more conserved than non phosphosites. Multiple phosphorylation sites could be compensatory for loss of one phosphorylation site. Therefore it is advantageous. If multiple phosphorylation sites have different roles (usually expected), loss of particular site could have deleterious effect.