One of the great events, near or at the orgin of life, was the advent of membranes- stable, flexible, but also rather tough structures build from amphipathic molecules, with water-loving head groups at one end and water-repellent, oil-like chains elsewhere. They sandwich together spontaneously to make the membrane (bilayer) sheet, which constitutes a separate phase from both the outside and inside of the cell. Getting across it is impossible for many molecules, which is highly protective, but has also necessitated a large zoo of transporters, channels and other mechanisms for transactions cells need to make with the outside.
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| Typical membrane, with a hydrophobic, oily interior that keeps it structurally coherent and impermeable to most aqueous substances. Note that it is, on a molecular scale, quite thick- bigger than most proteins. |
It has gradually become apparent that the nucleus (whose envelope is a double membrane and which was borne of another great event in life- the origin of eukaryotes) harbors quite a variety of other phases of macromolecules, constituting zones, globs, speckles, assemblies- organelle-like structures that make study of the nucleus rather interesting. The story begins with the nuclear pore, which is where any moderate to large size molecule, up to partially constructed ribosomes, has to go to enter or leave the nucleus. Such cargo typically has a short segment in its protein chain that serves as a "signal", either for nuclear export or import. These signals bind to specialized transporter proteins which themselves have an unusual decoration of hydrophobic protein segments (HEAT repeats). The nuclear pore is lined with proteins carrying another decoration, forming an unstructured hydrophobic and homophilic mesh or gel of FG-repeats (named for their composition of phenylalanine and glycine) inside the pore. The transporter HEAT repeats can bind weakly, but specifically, to these FG-repeats, or perhaps better, melt into them, and thus pass easily through the pore. It is a very clever scheme for controlling transport tightly with a mechanism that costs virtually no energy, since the transport is passive, going down the various molecules's concentration gradients.
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| Diagram of one nuclear pore complex. showing especially the mesh of FG-repeat protein tails that compose its interior and fringes. These interact with compatible transporter molecules to let large proteins and complexes through by selective diffusion. |
But that is not all. The nucleus has long been known to have a large zone, the nucleolus, where ribosomal RNA genes are transcribed and where much of the assembly of ribosomes takes place. It is a dense mass of DNA, RNA, and proteins specialized to these tasks, a veritable factory for making this most abundant and complex component of cells.
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| An electron micrograph of one ribosomal gene in the act of being transcribed. Each rRNA transcript is a separate "branch" on this Christmas tree, showing the conveyor belt/factory nature of the process. Image at top, tracing at the bottom. The field is about 2.5 micrometers. This is only one of many ribosomal generation processes taking place within the nucleolus. |
More recently, several other structures have been discovered in the nucleus, including speckles of RNA splicing components, Cajal bodies, PML bodies, paraspeckles, and others. And researchers have now realized that some transcriptional activation machinery forms similar blobs, called "super-enhancers". These have particularly high gene expression activity and seem to comprise a critical mass of regulatory RNAs, DNA-binding transcription factors, and a mess of mediators, histone modifiers, and other regulatory proteins in a sort of molten glob that segregates from the rest of the already-dense nuclear milieu. These are regarded as distinct liquid phases. Since DNA and RNA can bend, particularly between long-range enhancer regions and the promoter and coding regions of genes, it is possible to pack a lot of activity into a small, furiously active glob. And the high cooperativity that is implicit in the formation of such a glob is modeled, by a recent paper, to cause a sharp rise in transcriptional activation as well.
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| Model of condensed super-enhancers, (C, bottom), compared with run-of-the-mill enhancers, (C, top). Their transcriptional activity (red) is, due to their greater size and stability, likely to be higher and far more consistent than that of even strong enhancers. |
Why? One reason is that physical stability helps to keep the machine going, in contrast to usual interactions in the nucleus and elsewhere that are more sporadic, and fall apart as soon as they come together. Transcriptional activation, to take one example, relies on the coalescing (collusion, if you will!) of dozens of different proteins and complexes, all of which have to be available for other interactions as well, if dynamic gene regulation is to take place all over the genome. Most of these interactions are thus weak, so there is a critical mass (and perhaps composition) that distinguishes enduring, high-activity enhancer complexes, which can then be termed super-enhancer globs, from the normal form of enhancer that comes together on a far more temporary, ad-hoc basis. It is yet one more way, based on, but emergent from, the detailed composition of an enhancer, to turn up the gain on the target process that they regulate- transcription.
Different phases of matter thus have very significant roles in the cell, especially in the nucleus, allowing the establishment of mini-organelles / factories for operations that can be more efficient via the time-honored route of separation and specialization. They add to the sense of a sort of convergent evolution, since we already knew that there are conveyor belts, (DNA and RNA templates), just-in-time material and metabolic logistics, transport networks (actin, microtubules), and extraordinarily complex management methods in play.
- The pathological tau proteins in Alzheimer's bind to the nuclear pore proteins and gum up the works.
- One reason why our tax filing system is insane.
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- Krugman is has it sort of backwards- Medicare for all may be politically difficult, but other countries show it can be done. Accomplishing much via a Green New Deal, on the other hand, is, while critically important, also very difficult.
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- Veblen and the rot of inequality.
- Another view of MMT.
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