Tag Archives: Nature Chemistry

Brilliant structural work on the Arp2/3 complex with actin filaments and why it makes me depressed

The Arp2/3 complex of 5 proteins forms side branches on existing actin filaments.  The following paper shows its beautiful structure along with movies.  Have a look — it’s open access. https://www.pnas.org/doi/10.1073/pnas.2202723119.

Why should it make me depressed? Because I could spend the next week studying all the ins and outs of the structure and how it works without looking at anything else.  Similar cryoEM studies of other multiprotein machines are coming out which will take similar amounts of time.  Understanding how single enzymes work is much simpler, although similarly elegant — see Cozzarelli’s early work on topoisomerase.

So I’m depressed because I’ll never understand them to the depth I understand enzymes, DNA, RNA etc. etc.

Also the complexity and elegance of these machines brings back my old worries about how they could possibly have arisen simply by chance with selection acting on them.  So I plan to republish a series of old posts about the improbability of our existence, and the possibility of a creator, which was enough to me get thrown off Nature Chemistry as a blogger.

Enough whining.

Here is why the Arp2/3 complex is interesting.  Actin filaments are long (1,000 – 20,000 Angstroms and thin (70 Angstroms).  It you want to move a cell forward by having them grow toward its leading edge, growing actin filaments would puncture the membrane like a bunch of needles, hence the need for side branches, making actin filaments a brush-like mesh which could push the membrane forward as it grows.

The Arp2/3 complex has a molecular mass of 225 kiloDaltons, or probably 2,250 amino acids or 16 thousand atoms.

Arp2 stands for actin related protein 2, something quite similar to the normal actin monomer so it can sneak into the filament. So can Arp3.  The other 5 proteins grab actin monomers and start them polymerizing as a branch.

But even this isn’t enough, as Arp2/3 is intrinsically inactive and multiple classes of nucleation promoting factors (NPFs) are needed to stimulate it.  One such NPF family is the WASP proteins (for Wiskott Aldrich Syndrome Protein) mutations of which cause the syndrome characterized by hereditary thrombocytopenia, eczema and frequent infections.

The paper’s pictures do not include WASP, just the 7 proteins of the complex snuggling up to an actin filament.

In the complex the Arps are in a twisted conformation, in which they resemble actin monomers rather than filamentous actin subunits which have a flattened conformation.  After activation arp2 and arp3 mimic the arrangement of two consecutive subunits along the short pitch helical axis of an actin filament and each arp transitions from a twisted (monomerLike) to a flattened (filamentLike) conformation.

So look at the pictures and the movies and enjoy the elegance of the work of the Blind Watchmaker (if such a thing exists).

At a funeral

As I sat at a funeral for a friend’s wife 8 days ago, I thought how little the congregation (and most people) comprehend about we’ve been given.  The service was about eternal life and faith in it.  Faith isn’t easy apparently, and requires work to achieve and maintain.  While acquiring the chemistry, physics and math to understand molecular biology requires work, seeing it make accurate predictions and accepting the truth of the conceptual schemata required to even think of the experiments requires no faith at all

A bit about the deceased.  A lovely, talented, intelligent very beautiful woman who married a college classmate.  3 sons, 4 granddaughters as beautiful tall and graceful as she was. So she clearly has continuing (if not eternal) life.  When I first met her at our 50th college reunion, she appeared so young and so beautiful, that I immediately put my foot in my mouth and asked her if she was XXX’s second wife.

So I’m sitting there thinking about Duchenne dystrophy, and the transcription of the 2 million basepair gene for dystrophin with removal of 99.5% of the transcript before the mRNA is sent out the cytoplasm, wondering why we’re not all in wheelchairs, and how the congregation has no clue about any of this, as they sit there making and consuming their body weight in ATP over the course of a day.

Theodicy would no longer be a problem for the religious if they had any conception of just how miraculous our existence is.

Do molecular biologists have faith?  I think most do, since most appear to believe that intricate cellular metabolism and the molecular machines that make life possible just arose by random events with selection of the fittest.  Actually I don’t think that most think about these matters at all.  They certainly don’t publish about it, and doing so when I was a blogger for Nature Chemistry, got me bounced.

The more we find out about how we work internally, the more miraculous it becomes (to me at least) providing evidence for a creator.  It’s back to reverend Paley and the found watch.

I’ll close with this

It was pretty hard to be a doc back in the 60s and 70s watching good people suffer and die, and still conceive of a benevolent creator. “The Plague” by Camus with its hideous death scene of a child pretty much sums up the argument against one.

And yet, now that we know so much more molecular biology, cellular and organismal biochemistry and physiology, our existence seems totally miraculous. I at least have achieved a sense of peace about illness, suffering and death. These things seem natural. What is truly miraculous is that we are well and functional for so long.

You can take or leave the argument from design of Reverend Paley — here it is

“”In crossing a heath, suppose I pitched my foot against a stone, and were asked how the stone came to be there; I might possibly answer, that, for anything I knew to the contrary, it had lain there forever: nor would it perhaps be very easy to show the absurdity of this answer. But suppose I had found a watch upon the ground, and it should be inquired how the watch happened to be in that place; I should hardly think of the answer I had before given, that for anything I knew, the watch might have always been there. … There must have existed, at some time, and at some place or other, an artificer or artificers, who formed [the watch] for the purpose which we find it actually to answer; who comprehended its construction, and designed its use. … Every indication of contrivance, every manifestation of design, which existed in the watch, exists in the works of nature; with the difference, on the side of nature, of being greater or more, and that in a degree which exceeds all computation.”

The more chemistry and biochemistry I know about what’s going on inside us, the harder I find it to accept that this arose by chance.

This does not make me an anti-evoloutionist. One of the best arguments for evolution, is the evidence for descent with modification, one of its major tenets. The fact that we can use one of our proteins to replace one on yeast using our present genetic technology is hard to explain any other way.

Actually to me now, the existence or nonexistence of a creator is irrelevant. The facts of how we are built is not something you need faith about. The awe about it all comes naturally the more we know and the more we find out.