Coronavirus spike protein morphs into 10 different shapes to invade cells
These changes exposes more surfaces to potentially target with therapeutics.
The novel coronavirus uses its "spike proteins" to latch onto and invade human cells. But to do so, the spikes morph into at least 10 different shapes, according to a new study.
At the start of the pandemic, scientists rapidly identified the structure of the spike protein, paving the way to target it with vaccines and other drugs. But there's still so much scientists don't know about the interaction between the spike protein and the "doorknob" on the outsides of human cells — called the ACE2 protein. For instance, they aren't sure what intermediate steps the protein takes to kickstart the process of fusing to, and then opening the cell, ultimately dumping viral material into the cell.
"The spike protein is the focus of so much research at the minute," said co-lead author Donald Benton, a postdoctoral research fellow at the Francis Crick Institute's Structural Biology of Disease Processes Laboratory in the United Kingdom. Understanding how it functions "is very important because it's the target of most of the vaccination attempts and a lot of diagnostic work as well."
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To understand the process of infection, Benton and his team mixed human ACE2 proteins with spike proteins in the lab. They then used a very cold liquid ethane to rapidly freeze the proteins such that they became "suspended in a special form of ice," Benton told Live Science. They then put these samples under a cryo-electron microscope and obtained tens of thousands of high-resolution images of the spike proteins frozen at different stages of binding to the ACE2 receptors.
They found that the spike protein undergoes shape changes as it binds to the ACE2 receptor. After the spike protein first binds, its structure becomes more open to allow for more binding (imagine how much easier it would be to hug someone if they opened up their arms). The spike protein eventually binds to ACE2 at all three of its binding sites, revealing it's "central core," according to a statement. This final structure likely allows the virus to fuse to cell membranes.
"It's a very complicated receptor binding process compared to most virus spike proteins," Benton said. "Flu and HIV have a more simple activation process." The coronavirus is covered in spike proteins, and it's likely only a small fraction of them go through these conformational changes, bind to human cells and infect them, Benton said.
"We know that the spike can adopt all these states that we were talking about," said co-lead author Antoni Wrobel, who is also a postdoctoral research fellow at the Francis Crick Institute's Structural Biology of Disease Processes Laboratory. "But whether each of the spikes adopts all of them we can't say because we can see only kind of snapshots."
The spike protein is very quick to change. In the lab, the spike can morph into all of these different conformations in less than 60 seconds, Wrobel told Live Science. But "this will be very different in a real infection; everything will be slower because the receptor will be stuck on the surface of a cell so you have to allow time for the virus to diffuse to this receptor," Benton said.
Why does the spike protein go through this many conformational changes to infect a cell? It "may be a way of the virus protecting itself from recognition by antibodies," Benton said. When the spike protein is in its closed states, it hides the site that binds with the receptor, maybe to avoid antibodies coming in and binding to that site instead, he said.
But "it's very hard to know," Wrobel said. In any case, this research reveals more surfaces on the spike protein that are exposed during infection — as different shapes reveal surfaces once thought hidden. Researchers can then potentially develop vaccines to target these surfaces. "We can then start to think about therapeutics that would fit somewhere either in the receptor surface or somewhere in the spike itself that then act as drugs," Wrobel told Live Science.
Wrobel and Benton hope to figure out why the coronavirus goes through so many conformational changes, how that compares to other coronaviruses and if these changes might help explain why this new virus spreads so easily.
The findings were published Sept. 17 in the journal Nature.
Originally published on Live Science.
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Yasemin is a staff writer at Live Science, covering health, neuroscience and biology. Her work has appeared in Scientific American, Science and the San Jose Mercury News. She has a bachelor's degree in biomedical engineering from the University of Connecticut and a graduate certificate in science communication from the University of California, Santa Cruz.
By Harry Baker
By Sarah Moore
"Why does the spike protein go through this many conformational changes to infect a cell? It "may be a way of the virus protecting itself from recognition by antibodies," Benton said. When the spike protein is in its closed states, it hides the site that binds with the receptor, maybe to avoid antibodies coming in and binding to that site instead, he said."
It seems unlikely that hiding from antibody responses is the reason for the conformational changes since, according to the article, the changes occur only after the spike has made contact with ACE2 and begins the changes to expose these new sites :
"They found that the spike protein undergoes shape changes as it binds to the ACE2 receptor. After the spike protein first binds, its structure becomes more open to allow for more binding..."
Since the changes appear to occur only after contact with ACE2, it seems unlikely that a vaccine for those "hidden" regions of the spike would be viable. Based on the article, such regions are not usually exposed, except during the conformational changes which occur during binding - likely too late to promote antibodies, or prevent infection. In any event, it is interesting, and spooky, that the spike undergoes such changes in order to deliver the viral genome.
Perhaps using a soluble, inactive ACE2 "mimic protein" would trick the spike into latching on to a "dead-end receptor", preventing it from entering a cell. Getting the spike to initiate these conformational changes before it can bind to the real receptor may severely limit its ability to infect cells and replicate. However, creating such a "mimic" may not be so simple. But if one could produce such a recombinant protein in large amounts, and it is safe, it could provide a cure if it is present for sufficient duration to eliminate an active infection.
I haven't even basic knowledge of the processes you cite but my lizard brain knows that you are on to something. Please pursue your line of thought. We need all the intelligent help we can get.
As long as the fake "ACE2 trap proteins" are not toxic, there is a reasonable chance this could work. But the trap protein would have to be soluble, and so will not have the identical structure as the original, which is membrane-bound. One would have to be certain in its design that it does not itself illicit an antibody response, which would neutralize it rather quickly. It certainly looks good for a look-see from some high-brows in protein-virus interactions!
And technically, viruses are not poisons, but it sure seems reasonable to call them that, the little creeps.
Maybe we should dumb-down the terms a little so that non-scientists like me (not to mention our POTUS) can stay on the same page as the experts during life-or-death discussions about disease, public health, allocation of medical resources, and the costs/benefits of adequate medical care for the masses.
Please don't take my remarks as cynical or obstructionist. I'm just a fairly reasonable and bright old lady trying to understand. I'm honored that you took the time to respond to me. Here's to peace, love, and knowledge!
It does not seem like an ACE2 "trap" would be toxic but we would not know unless it is tried. The real ACE2 is membrane-bound, so it does not float around in your blood. The trap would have to be inactive (no enzymatic activity) and soluble for maximal impact, and this means a "new" protein in circulation, and a lot of it to be effective.
The real ACE2 is membrane-bound, and has at least two major "domains": the internal membrane domain, and external ACE2 domain - the latter being the "working end". The only obvious way to make this work is to replicate the gene coding for the external enzymatic ACE2 domain, the part which the virus binds to. That part of ACE2 would make up the "trap", but it means that some part of the trap's surface would be new to our system - that part which was contacting with the membrane-immersed domain of the real ACE2. Making this work depends largely on the overall structure of the real ACE2 - the two domains must be mostly separate from each other.
It might be possible to mask this new area to prevent it forming antibodies, which would ruin the chances of this working. And of course the trap protein would have to retain its original conformation that it has in the membrane-bound form, also not an easy thing to accomplish.
And just a heads up - viruses are not living organisms. They are little molecular machines with genetic code and some proteins. You are right about them being here longer than we have. They almost certainly arose early in the history of life, probably evolving from mechanisms used in those early life forms, and going rouge. You know how you don't like horrible relatives visiting. Viruses are in the same category.
And it is a pleasure conversing with someone like you who is interested in science and can post rational commentary. It also gives my mind exercise to recall aspects of protein structure and function critical for any good biochemist!
Thank you for clearing up the nature of viruses. I've always assumed they were a form of life. It's scary to think how devastating they can be, considering that they are not even alive! They certainly seem somehow to have evolved processes for ensuring their own replication and endurance in the world, and that makes them seem very alive, almost sentient, indeed.
I am going to study what you have written until I can envision all the moving parts. Then I think I'll better understand the successes and failures of the interventions under development. Please keep posting! We really need the insights of real-life experts, including a healthy bit of devil's advocacy, in these unsettling times.
No choice based on what I just discovered. Before, it was a lot of conjecture, with no knowledge of the ACE2 protein structure. The probability of this working just went up substantially! Was unaware of the ACE2 structure, so ran a search using nih.gov in the search to go directly to the most important data.
Below is a NIH link to a scientific article referencing ACE2's structure and its interaction with the original SARS virus's spike protein. Thought you might like to read through a real set of data, and look at the neat pictures of the ACE2 protein structure. Of course most people will not understand some of this, but there are places where it is clear what they are going about.
What matters most here is that we have the structure of ACE2 at atomic resolution, which is the ultimate. So this is all well known and would come in very handy if someone tried this notion of using a modified ACE2 viral "trap".
Of particular note is figure 6, which shows that most of the ACE2 protein is sticking way out into solution, while only a small part of it anchors the entire protein to the membrane. This is very good news for making a trap out of the large, virus binding component of ACE2, sticking out as it does. It is almost enough to give one goose bumps, this looks so good! But we must remember that many good ideas have come to naught. Time will tell, perhaps! It is not likely I am the only one to think of this.
This has been a very fruitful discussion, Wanda. Thanks for perking my interest. Please keep posting!
from nih.gov :
Not into the social media aspect. Too many people with too many questions and issues. Don't have the time. This is as close to social media as my PCs get.
Am compelled to believe others have or will think of this idea. They have had a lot of time to ponder it, and there are plenty of clever people out there. Well, a few any way! Perhaps something will come of it when the right person reads this thread?!
And there are significant hurdles. Lots of research when the vaccine is much more likely. The ACE2 trap idea is a good plan B though. Somebody has to check it out. Might have to call around to some professionals and see what if anything has been tried.
Thanks again for your ideas and exchanges. There may be more to follow once this initial publication of the structural changes has sunk into all the experts. Sure got my attention!
Another part about the trap that is unique is that the virus is not likely to find a way to mutate around it. The ACE2 protein is human and is not prone to mutate like the virus. Any significant mutations in those inner binding sites of the spike protein would be rejected by the trap in favor of the higher binding original virions that caused the infection, meaning the trap would continue to work against all variants of the virus, now or in the future. One might need to receive another shot of traps if the virus comes back in a year or two (assuming it ever disappears), or a gene could be inserted that produces the traps.
They already have those genes for antibodies, and some are being used to allow anti SARS-CoV-2 antibodies to be produced by muscle cells. These antibodies' genes are cloned from people who were already infected and produced neutralizing antibodies. This is a form of "donor DNA". Very unique, but not likley a long term cure.
We will keep an eye on things and see what develops.