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).

A letter to the PNAS editor which will never be published

“Starting out the year 2021 by looking back at the year 2020 might seem like an exercise in masochism, given the horrific loss of life, the untold economic hardships, the resurgence of white supremacy across the country“

As a good friend and college and grad school classmate of Nick Cozzarelli who edited PNAS for 10 years, I find this statement by the current PNAS editor — May Berenbaum, unhelpful, unscientific and frankly appalling. Had Nick not been taken from us far too soon in 2006 by Burkitt’s lymphoma, he’d likely be editing PNAS still. Does the editor’s statement rank with any of Nick’s work on DNA gyrase or DNA topology?

It is an exercise in the religion of political correctness, showing adherence to its current catechism, for political correctness and wokeness is nothing but a religion for the secular.  In our town expressions of faith abound on front lawns complete with statues of the virgin and signs proclaiming “we believe in science’. There really is no difference.

How a hack like Berenbaum got to be editor is beyond me, given the women scientists of great stature around (Doudna, Ghez, Randall).

Is Nick — https://en.wikipedia.org/wiki/Nicholas_R._Cozzarelli — an example of white supremacy? Nick’s father was an immigrant shoemaker from Jersey City and Nick worked his way through Princeton waiting on tables in commons.