Never presume that the list of molecular machines in the cell is exhausted by the bacterial flagellum, kinesin, and ATP synthase. Those are just three that we have animated thus far. There are so many thousands of machines in living cells, we don’t stand a chance of running out of examples to talk about. Here’s a new one: the “eukaryotic replicative CMG helicase.” Call it CMG helicase for short (the -ase suffix indicates that it operates on a helix, namely the DNA double helix).

Of the many kinds of helicase enzymes that operate on nucleic acids, this one is important right before cell division, when the cell must replicate all of its genetic code. Since DNA consists of two strands, something needs to break them apart so that spare nucleotides can pair up with each side, producing two strands. That’s the job of CMG helicase. You could also compare it to a sewing machine, but an “unsewing” machine would be more accurate. As it passes by, it unzips the DNA strand with a unique rocking mechanism.

Research from Stony Brook University describes how it works. The authors’ preferred metaphor is a “pumpjack” like those machines that rock up and down as they pump oil out of a well. New close-up images of the helicase showed that it takes on two shapes as it moves down the DNA:

Using computer software to sort out the images revealed that the helicase has two distinct conformations — one with components stacked in a compact way, and one where part of the structure is tilted relative to a more “fixed” base.

The atomic-level view allowed the scientists to map out the locations of the individual amino acids that make up the helicase complex in each conformation. Then, combining those maps with existing biochemical knowledge, they came up with a mechanism for how the helicase works.

“One part binds and releases energy from a molecule called ATP. It converts the chemical energy into a mechanical force that changes the shape of the helicase,” Li said. After kicking out the spent ATP, the helicase complex goes back to its original shape so a new ATP molecule can come in and start the process again.

“It looks and operates similar to an old style pumpjack oil rig, with one part of the protein complex forming a stable platform, and another part rocking back and forth,” Li said. Each rocking motion could nudge the DNA strands apart and move the helicase along the double helix in a linear fashion, he suggested. [Emphasis added.]

They also liken the action to an inchworm. To each his own. Since pumpjacks don’t go anywhere, and inchworms move but don’t change anything, probably a sewing machine analogy is more appropriate. Video clips in the article show how the enzyme moves along the helix, rocking as it goes.

As the helicase moves along, it interacts with other parts similarly to how a sewing machine interacts with the thread, the needle, and the cloth. Notice the complexity described in the paper in Nature Structural and Molecular Biology.

The CMG helicase is composed of Cdc45, Mcm2-7 and GINS. Here we report the structure of the Saccharomyces cerevisiae [yeast] CMG, determined by cryo-EM at a resolution of 3.7-4.8 Å. The structure reveals that GINS and Cdc45 scaffold the N tier of the helicase while enabling motion of the AAA+ C tier. CMG exists in two alternating conformations, compact and extended, thus suggesting that the helicase moves like an inchworm. The N-terminal regions of Mcm2-7, braced by Cdc45-GINS, form a rigid platform upon which the AAA+ C domains make longitudinal motions, nodding up and down like an oil-rig pumpjack attached to a stable platform. The Mcm ring is remodeled in CMG relative to the inactive Mcm2-7 double hexamer. The Mcm5 winged-helix domain is inserted into the central channel, thus blocking entry of double-stranded DNA and supporting a steric-exclusion DNA-unwinding model.

The Stony Brook research team studied this molecular machine in yeast cells, but all eukaryotes rely on it, including humans. Is it important? You bet. More:

“DNA replication is a major source of errors that can lead to cancer,” explained Li, a Professor in the Department of Biochemistry & Cell Biology at Stony Brook University, a scientist at Brookhaven Lab, and lead author of the paper. “The entire genome — all 46 chromosomes — gets replicated every few hours in dividing human cells,” Li said, “so studying the details of how this process works may help us understand how errors occur.”

Fortunately, errors are very rare. Lee Spetner in his book Not by Chance says that because of molecular proofreading, the error rate is one in a hundred billion. That’s “like one error in fifty million pages of typescript,” he says. “Fifty million pages are the lifetime output of about a hundred professional typists” (p. 39).

Yet the machinery is much more rapid than the best typist. It rocks! — not like the slow, lumbering mechanism of the oil pumpjack, but at blinding speed. Jonathan M. wrote here at Evolution News that DNA replication works at 749 bases per second with an error rate of 10^-7 to 10^-8. Yet the cell performs this feat in just hours, trillions of times in your body. Nor does it work alone. All the other machines in the DNA replication factory keep up with it, bringing in nucleotides, proofreading them, and fastening the new helices together.

There are other helicases that have inspired machine analogies:

• The torque wrench that repairs DNA

• The train engine that exposes a broken section of track

• The oscillator that pulls bacteriophage DNA strands apart like a rotary engine

• The jackhammer zipper that opens up double-stranded RNA

What’s fundamentally important for philosophy of biology is that these really are machines. They may not look like man-made machines, but they fit the definition. They use energy to perform work in a highly detailed and specific manner. These are not your normal chemical reactions, where molecules simply bump into each other and exchange electrons. These machines have precise shapes with moving parts. They operate on other structures. And most importantly, their parts and functions are dictated by coded instructions. It’s phenomenal that those instructions code for the creation of machines that come back to work on the coded instructions, making sure they are intact and error-free. How cool is that?

Think about these machines at work in your own body right now. Somewhere in your brain, a cell is dividing. That cell needs to continue operating while its DNA is being replicated at about 750 bases per second. Multiple CMG helicases have to know where to unzip the DNA without interrupting genes that other machines are transcribing. Machines keep track of what parts are done and what parts remain to be done. Other machines check for errors in the copies. Machines supervise the operation, setting checkpoints that don’t let cell division proceed until all requirements are met.

This is all happening while the cell is at work. It’s mind-boggling. Could humans duplicate every part of a factory while it is in full operation? Could they duplicate every thread in a suit of clothes while it is being worn? Word pictures fail to capture the complexity of such things. They don’t just indicate design; they scream design.

Image: Pumpjacks, by Arne Hückelheim (Own work) [CC BY-SA 3.0 or GFDL], via Wikimedia Commons.