Nucleosome cores are screws, not cans or bubbles

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Each one of your cells is too small to be seen with the naked eye. Remarkably, each one has 6 feet of DNA packed inside a smaller compartment (nucleus) within the cell. Very complicated data has solved this mystery…can the data be presented in an attractive and understandable way?

The more you learn about biochemistry, molecular biology, and proteins, the more you will see a basic principle appear over and over again: ‘shape drives function.’ One of my favorite examples is aquaporin [1], a type of protein that clusters into a tube that acts like a straw poking through your cell membranes. These little straws allow water and small molecules to pass into and out of the cell.

Of course my all time favorite example is related to chromatin, the protein-DNA complex that makes up your chromosomes. My lab invents ways to change chromatin for cancer treatment and tissue regeneration. Wait, protein-DNA complex? Yes, proteins (one type of large molecule) interact with DNA (a different type of molecule…the one carrying the genetic alphabet of A, T, C, G). Importantly, a specific type of protein called a histone (HIS-tone) plays a key role in packing 6 feet of DNA into a tiny nucleus.

Scientists (in particular, molecular biologists) reading this know that chromatin is old news. The earliest paper I recall from my PhD studies dated back to 1928 (Das heterochromatin der moose by Emil Heitz [2]). That’s “moss” in German, not the large furry animal. Heitz observed DNA packing inside of moss cells by using dyes and imaging equipment considered to be rudimentary by today’s standards.

Since then, we have used powerful techniques to “solve” chromatin: genetics to mutate (disrupt) it in living organisms, electron microscopes to chart its tiny bumpy surfaces, and crystallography and NMR to map the position of every atom within it. All of this research has led scientists to develop illustrations of what we think DNA packing looks like. I present to you ladies and gentlemen a representation of data, painstakingly collected by dozens of scientists over decades, as the can model!

Histone_cans_1
Can model. Histones, yes we “can.” DNA is shown as a blue line. About 200 base pairs of DNA is wrapped twice around a core of histone proteins. This unit is called a nucleosome.

Data – measurements taken from experiments done on a subject of study, such as chromatin.
Model – a drawing, sculpture, digital rendering, etc. of what you think the data says about the thing you are studying.

Okay, not very impressive-looking, but this is just a cartoon abstraction. Scientists use cartoons like these in research reports when showing every single atom in a molecule is too messy and confusing. Although popular, I think that the can model is so abstract that it is confusing. Is that one big cylindrical histone? How does the DNA ‘know’ to always wrap in that titled coiled way around the can?

Slightly more sophisticated than the can model is the bubble model. The bubble model shows us that the cylinder in the middle is actually a cluster of eight histone proteins. Some bubble models even have little noodles poking out to represent  “histone tails”…the regions that carry different chemical ‘flags.’ A cover illustration I created for JBC follows this style somewhat (cans with tails). I’ve noticed more and more bubble models in papers and presentations, perhaps due to more intuitive graphic design programs and more discoveries about histone tails.

Histone_bubbles_1
Bubble model. The core of each nucleosome is made up of eight individual histones, shown here as bubbles with tails.

Pretty great, I thought, until I saw data reported in 1997 by the brilliant and talented Karolin Luger (lead author) [3]. Her model showed the histones situated in 3D space in a stack like a spiraled staircase. I had an epiphany: the histones form a little (partial) screw! Then, I ran across the following mind-blowing, amaze-balls digital animation produced by WEHImovies. It looks like each outer-surface on the histone “screw” grabs a piece of DNA and pulls the DNA into a spiral.

I was inspired to start working on a new cartoon that is simple, yet conveys an important feature: the spiral staircase structure that guides DNA winding. I present to you, the screw model; it shows the histones arranged into a solenoid-ish, screw-like, donut thingy that winds the DNA in a spiral.

Histone_screw_1
(A) Cartoon of K. Luger’s 1997 X-ray crystal structure data for the histone complex. Each “Z” with a tail represents the general shape of an individual histone protein. (B) Abstraction of the histone complex as three “layers”. Each layer represents a sub-complex that grabs and wraps DNA. (C) Pathway of DNA wound around the histone complex.

Beautiful! As an artist and a scientist, I find this version very satisfying. Stay tuned for more illustrations of proteins involved in chromatin: natural proteins that add ‘flags’ to and grab onto histone tails, and the synthetic proteins we have built to mimic the latter.

REFERENCES

  1. Aquaporin. Wikipedia, the free Encyclopedia. https://en.wikipedia.org/wiki/Aquaporin
  2. Heitz, E. (1928) Das heterochromatin der moose. I. Jahrb. Wiss. Botanik. 1928; 69: 762–818
  3. Luger K1, Mäder AW, Richmond RK, Sargent DF, Richmond TJ. (1997) Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature. 389: 251-260.

 

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