Tuesday, November 03, 2009

Believing six impossible things before breakfast

Here is a little digression for your breakfast edification.

A typical animal cell is about 16 micrometers (16 millionths of a meter) in diameter. Thinner than a sheet of tissue paper. Tinier than the period at the end of this sentence. There are ten trillion or so cells in your body.

Lot's of stuff packed into each cell, including an arm's length of DNA, the code of life. Yes, really! I know it sounds impossible that an arm's length of anything would fit in such a small space, with room left over for other stuff, but it does. And it's not just sitting there. Tiny protein-based "motors" crawl along the strands of DNA, transcribing the code into single-strand RNA molecules, which in turn provide the templates for fabricating the proteins that build and maintain our bodies. Other proteins help pack DNA neatly into the nuclei of cells and maintain the tidy chromosome structures. Still other protein-based "motors" are busily at work untying knots that form in DNA as it is unpacked in the nucleus and copied during cell division. Others are in charge of quality control, checking for accuracy and repairing errors. Working, spinning, ceaselessly weaving, winding, unwinding, patching, repairing -- each cell like a bustling factory of a thousand workers. Ten trillion cells humming with the business of life.

All this in a cell smaller than this period.

And now I see an article in a recent issue of Nature (8 October): "Nucleation, propagation and cleavage of target RNAs in Ago silencing complexes." Here is the abstract. Don't worry about understanding it; I don't. Just scan it.
The slicer activity of the RNA-induced silencing complex resides within its Argonaute (Ago) component, in which the PIWI domain provides the catalytic residues governing guide-strand mediated site-specific cleavage of target RNA. Here we report on structures of ternary complexes of Thermus thermophilus Ago catalytic mutants with 5'-phosphorylated 21-nucleotide guide DNA and complementary target RNAs of 12, 15 and 19 nucleotides in length, which define the molecular basis for Mg2+-facilitated site-specific cleavage of the target. We observe pivot-like domain movements within the Ago scaffold on proceeding from nucleation to propagation steps of guide-target duplex formation, with duplex zippering beyond one turn of the helix requiring the release of the 3'-end of the guide from the PAZ pocket. Cleavage assays on targets of various lengths supported this model, and sugar-phosphate-backbone-modified target strands showed the importance of structural and catalytic divalent metal ions observed in the crystal structures.
And just to give all those words a bit of substance, here is one of the diagrams that accompany the article (click to enlarge).

It seems impossible that anyone could know in such detail what's going on at such a tiny scale. For the first time in human history we are learning about the basic machinery of life in action, machinery that not so long ago we had no idea existed, machinery that is in one sense stunningly simple (that 4-letter code of DNA for all of life, that elegant double helix), and in another sense is so staggeringly complex that we wonder that it works at all, so reliably, for such a long time. The unceasing chemical dance that makes you you and keeps you you. And we sit here sipping our coffee, ten trillion cells, a seething miracle -- all unawares.