Archive Classic: 2003 News on Cells

Here are two CEH articles from 20 years ago that were lost during the website upgrade. They are still interesting to read.

Note: some embedded links may be broken.

A Self-Regulating Recycling System Found in the Cell   10/07/2003
Cells are not watertight sacks; they import and export things. But they are not leaky sacks either: everything coming and going is authenticated by sophisticated mechanisms. Small packages, like water molecules or individual proteins, have specially-designed channels embedded in the cell membrane that check their credentials and make them run an electronic gauntlet (see 03/12/02 headline, for instance).²  Larger packages, however, have a surprising method of making their entrance: they dive in and get wrapped in geodesic spheres. The cell membrane neatly reseals itself around the point of entry, which occurs only where specialized receptors allow it. This is called endocytosis (for cargo on the way in) and exocytosis (on the way out).

The geodesic spheres are made up of a three-armed protein called clathrin. The clathrin molecules envelop the cargo, forming a crystalline polyhedron around it. (You absolutely have to see this cool animation by Allison Bruce of Harvard, showing clathrin forming a spherical vesicle; incredible.) Once the cargo in its crystalline cage has been safely ferried to its destination, the clathrin molecules disassemble and are available for re-use. (This process, and much more, is beautifully illustrated in the award-winning animated short film Voyage Inside the Cell).  Exocytosis is the process in reverse, when the cell needs to export cargo to the outside: for example, when a nerve cell needs to send neurotransmitters to another neuron.  A host of helper enzymes are involved in making both processes work.

“Clathrin-mediated endocytosis is one of the primary mechanisms by which eukaryotic cells internalize nutrients, antigens, and growth factors and recycle receptors and vesicles,” begin a team of Pennsylvania scientists in a paper in the Oct. 3 issue of Cell.¹  But it should be obvious that the amount of cargo coming in must balance that going out, or else the cell will burst or shrivel. “A tight balance between synaptic vesicle exocytosis and endocytosis is fundamental to maintaining synaptic structure and function,” they write, speaking especially of neurons that execute these processes continuously in the central nervous system and the brain. How can the cell maintain this balance?

These scientists discovered an automatic regulatory process that ensures the materials are recycled properly. A protein called endophilin, a key regulator of the endocytosis process, has two states: open and closed. In the open state, it attaches to the interior side of voltage-gated calcium channels (these are membrane turnstiles that allow only doubly-ionized calcium to pass through). Here, it somehow recruits other protein machines needed for the endocytosis operation. When the calcium concentration reaches 1 micromolar, the endophilin switches into the closed position. Then, it detaches from the calcium gate, “which would presumably allow the liberated endophilin and dynamin [another helper enzyme] to become actively involved in endocytosis immediately after SV [synaptic vesicle] exocytosis.” A similar self-regulating system had been known for exocytosis, but this is the first time a mechanism has been found to regulate endocytosis: “By coupling tightly to both the exocytotic and endocytic machineries,” they conclude, “voltage-gated Ca²⁺ channels are thus uniquely positioned to coordinate the SV recycling process.” Their model, however, is just a rough picture of a much more elaborate process scientists are just beginning to understand.

¹Yuan Chen et al., “Formation of an endophilin-Ca²⁺ Channel Complex Is Critical for Clathrin-Mediated Synaptic Vesicle Endocytosis,” Cell Vol 115, 37-48, 3 October 2003.
²Two American scientists just received the Nobel Prize in chemistry October 8 for their work that revealed the structure and function of the water and ion channels in the cell membrane.  See story in FoxNews.

What can you say but “Wow!” Cell operations are so amazing. The authors use the word machinery 14 times, and not once use the word evolution or give any clue how all these parts “emerged” from any simpler cell.

All the parts of this system have to be present and functioning: the voltage-gated calcium channels (voltage-gated: imagine that!), the endophilin and dynamin and other helper enzymes, the clathrin, and much more. Mechanisms must ensure that only authenticated cargo is allowed in, and that the breach is resealed rapidly without leakage. The helpers have to be recruited to the spot ahead of time, so they are ready for the operation. The endophilin enzyme has to have the right shape to open and close when the concentration of calcium is just right.  The ingredients must be recycled and kept in balance.

Each component is a complex system in itself. Each protein is a large molecule of precisely-sequenced amino acids. This is a system of complex systems. How could such a smooth, efficient, functional system evolve? A mutation in just one component can break the whole process: in fact, that’s how they learned about it, by artificially mutating a component, which drastically impaired the operation.

Pause and wonder: you can read and think about this right now because endocytosis and exocytosis is going on in your brain millions of times a second.

Mitochondrial Ribosome Structure Casts Doubts on Endosymbiont Theory    10/07/2003
Have you heard the story that early cells swallowed other ones and made them their slaves? That is supposedly where mitochondria came from, but an article in the Oct. 3 issue of Cell reports that there are some big differences between the mitochondrial ribosomes of eukaryotes and those of bacteria, the presumed captives.

Manjuli Sharma et al.¹ determined the structure of the eukaryotic mitochondrial ribosome (mitoribosome) for the first time. These ribosomes (sites of protein synthesis) differ from those in the cytosol, because they produce 13 specialized proteins dedicated primarily to the production of ATP.

According to several genomic analyses, mitochondria are believed to have arisen from an early endosymbiotic event between a eubacterium and its host cell …. Therefore, it has generally been expected that the mitoribosome will display greater structural and functional similarities to a bacterial ribosome than to a eukaryotic cytoplasmic ribosome.  (Emphasis added in all quotes).

They found, “However, the RNA and protein composition of the mitoribosome differs significantly from that of bacterial ribosomes.” Whereas the small subunit has 950 nucleotides and 29 proteins, the bacterial counterpart has 1542 and 21, respectively.  The large subunit has 1560 nucleotides and 48 proteins, but the bacterial counterpart has 120 + 2904 nucleotides in two units, and 33 proteins. “Thus, the protein-to-RNA ratio is completely reversed in the mitoribosome (69% protein and 31% RNA) relative to bacterial ribosomes (33% protein and 67% RNA),” they note. Even among the roughly half of the proteins in the eukaryotic mitoribosome that have homologs in bacteria, they are usually significantly larger. And the whole ribosome, though larger, is more porous than the bacterial one.

The rest of the paper describes the functional units of the mitoribosome. They found exquisite entrance tunnels for the transfer RNA and messenger RNA, and precision exit tunnels for the nascent polypeptides. They feel their analysis “provides new insights into the structural and functional evolution of the mitoribosome.” But the paper also describes large differences between the mitoribosomes and the ribosomes in the rest of the cell:

Furthermore, unlike cytoplasmic ribosomes, the mitochondrial ribosome possesses intersubunit bridges composed largely of proteins; it has a gatelike structure at its mRNA entrance, perhaps involved in recruiting unique mitochondrial mRNAs; and it has a polypeptide exit tunnel that allows access to the solvent before the exit site, suggesting a unique nascent-polypeptide exit mechanism.

It appears, therefore, that these three classes of ribosomes are quite different from each other. This is probably due to the different jobs they have to do, as expressed in the title of their paper: the component proteins of the mitoribosome suggest they have “an expanded functional role” over their counterparts.

¹Sharma et al., “Structure of the Mammalian Mitochondrial Ribosome Reveals an Expanded Functional Role for Its Component Proteins,” Cell Vol 115, 97-108, 3 October 2003.

This paper assumes evolution in contradiction to the data. They found no intermediates, and no support that this complex molecular machine evolved from bacteria. They provide no plausible mechanism by which significantly different proteins, in significantly different amounts, could produce a significantly different structure in stepwise fashion without breaking the machinery in the process. Yet to get all these differences at once would be a miracle.

The structure they examined doesn’t match the glittering generality that this precision device happened once upon a time when a eukaryotic cell decided to invite a bacterium inside for lunch. Even though their mitochondria have similar functions, their structures are completely different.

If we stuck to the observational facts, we would no sooner assume one evolved from another as we would assume a Ferrari evolved from a Volkswagen. Like cars, that have finely machined parts that fit together, these different models of ribosomes are composed of hundreds of parts arranged in very specific shapes (which are dependent on the precise sequences of their building blocks), and these shapes all have a critical role in the overall function: reading a DNA transcript (on messenger RNA), and producing a protein.

These authors assume evolution but demonstrate the opposite. “Distinct topological differences in the mRNA entry and polypeptide exit sites, as compared to the corresponding regions in cytoplasmic ribosomes, suggest mechanistic divergence of protein synthesis on the mitoribosome,” they say, implying common ancestry, and elsewhere they are even more explicit: “These observations indicate that during the evolution of the mitoribosome, proteins took over some of the functions of rRNAs, including much of their participation in the intersubunit communication.” Good grief, now we have proteins committing job theft. Most of the paper is good scientific observation with some nifty stereo pictures of the molecular machines. The evolutionary storytelling adds nothing but subtracts much.