Of what use is an inactive enzyme?

Why should a cell take the trouble make an enzyme protein with no enzymatic activity? It takes metabolic energy to store the information for a protein in DNA, transcribe the DNA into RNA and then translate the RNA into protein. Is this junk protein a la junk DNA? Not at all — and therein lies a tale.

All sorts of nasty bugs inveigle their way into cells, among them viruses (such as influenza) whose genome is made of RNA, rather than DNA. Not only that, but in many virus their genome is not single stranded (like mRNA) but double stranded with two RNA strands base paired to each other (just like DNA, except for an extra oxygen on the ribose sugars in the backbone).

Nucleated cells don’t contain much double stranded RNA (dsRNA) outside the nucleus, so it almost always means trouble. An extremely elegant mechanism exists to find and respond to such RNA. Recall that double helix molecules can reach enormous lengths.The 3.2 billion base pairs of our genome, if stretched out, would be more than a yard.

Well we have at least 4 genes which bind dsRNA and then signal trouble. They all make a molecule called 2′ – 5′ oligoadenyic acid (2-5A) from ATP, so they are called OligoAdenylate Syntheses (OASs). The 2-5A, once made wanders about the cell until it finds another enzyme called RNAase L. 2-5A binds to RNAase L causing it to dimerize and become active. RNAase L then destroys all the RNA in the cell, killing it along with the invading virus. Pretty harsh, but it’s one way to stop the virus from spreading and killing more cells.

A recent paper http://www.pnas.org/content/112/13/3949.full concerns OAS3, which has 3 catalytic modules rather than just one like most enzymes. Even worse, 2 of the 3 catalytic modules can’t make 2-5A (but they still can bind dsRNA). OAS3 is a large protein (over 1,000 amino acids), so it has some length to it. The 3 catalytic modules are spread out along OAS3 with the active catalytic module at one end and one of the inactive modules at the other.

The modules at both ends bind dsRNA, but only the active module makes 2-5A when it does. Interestingly, the inactive module binds dsRNA much more strongly than the active one.

OK, you’ve got the picture — what possible use is this rather Byzantine set up?

See if you can figure it out.

It’s incredibly clever and elegant, and shows the danger to regarding anything within the cell as functionless (or junk). Teleology rides supreme in molecular and cellular biology.

Give up?

OAS3 essentially acts as a molecular ruler making 2-5A only when long dsRNA (e.g. over 50 nucleotides long) binds to it. The inactive module gloms onto longish dsRNA, holding it tightly until till Brownian motion brings it to the other end of OAS3 activating the catalytic module to make 2-5A. This is good as the cell normally contains all sorts of shorter RNA duplexes (the binding of microRNAs to the 3′ end of mRNAs come to mind — but they are much shorter (22 nucleotides at most).

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