Category Archives: Molecular Biology

Watch the press

We are about to embark on a variety of social experiments, in removing the restrictions on our activities.  This will be accomplished many different ways, in many different locales (which is good, because if there ever was a country where one size does not fit all, it is the USA).  But beware of what you read about the effects. There are people who will be proved very wrong either way — if nothing happens, or if cases and deaths skyrocket.

It’s good to see that people are being explicit about their predictions.  Here are two, both of which can’t be right

https://www.theatlantic.com/health/archive/2020/04/why-georgia-reopening-coronavirus-pandemic/610882/ — Here’s how it begins —

Georgia’s Experiment in Human Sacrifice

https://www.theepochtimes.com/as-ccp-virus-brings-a-taste-of-fascism-trump-needs-to-end-us-overreaction_3330804.html

As CCP Virus Brings a Taste of Fascism, Trump Needs to End US Overreaction

Also beware of breathless reports of nothing happening in the first few days confirming that it was OK to lift restrictions, again because new cases will take a while to show up, and new deaths from the disease will take even longer.

They may be right, they may be wrong, but at least we’re about to find out.

 

Addendum 1 May: If you have the time, please read Matt Taibbi’s latest article — https://taibbi.substack.com/p/temporary-coronavirus-censorship.
It shows just how invested the ‘don’t relax restrictions’ side is in having the experiment fail.  Toward the end of Taibbi’s article you’ll find a series of quotes in January from the same bunch showing why you shouldn’t worry about the coronavirus.  I wish I’d saved them.  I knew better, because I’d been closely following what was going on in China  since 1 Jan because I have a son, daughter-in-law and two grandchildren living in Hong Kong. Here’s a link to that old post of 27 January — https://luysii.wordpress.com/2020/01/27/what-to-do-about-the-wuhan-flu/

Here is the last post on the subject.  Good luck to us all

Gentlemen, place your bets

It’s time for us all to think like a doc who’s ordered a bunch of tests on a fairly sick patient.  The good ones don’t wait for them to come in and then figure out what to do.  They usually concentrate on the worst cases and make plans.

Before going any further, please read the following paragraph. I’m sorry to keep putting this in, but I don’t want to leave anyone behind. Finding the actual genome (RNA in this case) of a virus in an individual  is like seeing a real bear up close and personal.  This can do you some damage.  In contrast, antibodies to the virus are made by an individual who has been infected by the virus in the past.  Antibodies (proteins) and genomes (RNA) are completely different chemically.      Antibodies are like seeing the tracks of the bear without the bear itself. You can’t see tracks without the bear having been present at some point in the past.

Well we’re in that situation in the USA.  Based on many studies now (California, New York State, Prison systems) the number of people who’ve been exposed to the virus enough to develop their own antibodies to it, is anywhere from 10 – 100 times greater than the number of people in whom the viral genome has been found.  This means that the vast majority of infections with the new coronavirus are asymptomatic.

We’ll have a more accurate picture shortly, but what do you think will happen when New York State (and probably everyone else) repeats the test for antibodies in a few weeks?

Place your bets.

Once you have an antibody to a bug, you have it (at least for a few weeks to months).  This is not true for the elderly and my wife had to be re-vaccinated for measles so she doesn’t give it to our grandkids should she be exposed again.

So repeating the prevalence of antibody studies should show an increasing percentage of people with the antibodies.  The bets have to do with how much increase we will see.  Will NY go from 13% to 26% or higher?  The experience in nursing homes and the disaster in the Soldier’s Home in Holyoke MA, shows that in a vulnerable group the infection rate can explode — https://www.masslive.com/news/2020/04/coronavirus-at-holyoke-soldiers-home-additional-veteran-dies-infection-remains-stable-over-3-days.html. Out of 210 veterans living there 66 have died of COVID19 and 82 more have been infected (showing the genome), since the first case was discovered 21 March.

Showing the conflicting evidence docs have to deal with all the time — consider the prisoner studies — https://www.reuters.com/article/us-health-coronavirus-prisons-testing-in/in-four-u-s-state-prisons-nearly-3300-inmates-test-positive-for-coronavirus-96-without-symptoms-idUSKCN2270RX.

It isn’t clear which test was being used (viral genome or antibodies to the virus).  But this is a younger and healthier population.  Very surprisingly in four state prison systems — Arkansas, North Carolina, Ohio and Virginia — 96% of 3,277 inmates who tested positive for the coronavirus were asymptomatic.

So if healthy people won’t be made sick, what will happen when restrictions on activity (both personal and business) are lifted as they will be shortly?   You have two conflicting pieces of evidence to help you place your bets.  Fortunately the country has not adopted a one-size-fits-all approach, and lots of different experiments of nature will occur.

New York is the epicenter, with the most cases and very high population density.  Symptomatic cases appear to have stabilized even with a 10fold higher transmission rate (as measured by antibody prevalence) than that measured by finding the viral genome itself.

What would be your guidance here?

It’s time to pay our respects to Dr. Janeway who first focused on the innate immune system 30 years ago — https://en.wikipedia.org/wiki/Charles_Janeway.  Obviously if we had to wait the week or so for antibodies to develop to fight off infections, we’d all be dead.  The innate immune system is much older evolutionarily than antibodies and starts working immediately.  We are still finding out how complex it is. https://en.wikipedia.org/wiki/Innate_immune_system.

Like everything else, the innate immune system weakens with age, possibly explaining the difference in clinical outcome between the vets at the Soldier’s home and the prison inmates.

It’s hard to place a bet when you’re wishing for the best possible outcome as are most of us. Some people are highly invested in the worst possible scenarios, particularly those who’ve predicted them.  My guess is that we won’t see a surge in fatal or symptomatic cases as things open up.  What’s yours?

Gentlemen, place your bets

It’s time for us all to think like a doc who’s ordered a bunch of tests on a fairly sick patient.  The good ones don’t wait for them to come in and then figure out what to do.  They usually concentrate on the worst cases and make plans.

Before going any further, please read the following paragraph. I’m sorry to keep putting this in, but I don’t want to leave anyone behind. Finding the actual genome (RNA in this case) of a virus in an individual  is like seeing a real bear up close and personal.  This can do you some damage.  In contrast, antibodies to the virus are made by an individual who has been infected by the virus in the past.  Antibodies (proteins) and genomes (RNA) are completely different chemically.      Antibodies are like seeing the tracks of the bear without the bear itself. You can’t see tracks without the bear having been present at some point in the past.

Well we’re in that situation in the USA.  Based on many studies now (California, New York State, Prison systems) the number of people who’ve been exposed to the virus enough to develop their own antibodies to it, is anywhere from 10 – 100 times greater than the number of people in whom the viral genome has been found.  This means that the vast majority of infections with the new coronavirus are asymptomatic.

We’ll have a more accurate picture shortly, but what do you think will happen when New York State (and probably everyone else) repeats the test for antibodies in a few weeks?

Place your bets.

Once you have an antibody to a bug, you have it (at least for a few weeks to months).  This is not true for the elderly and my wife had to be re-vaccinated for measles so she doesn’t give it to our grandkids should she be exposed again.

So repeating the prevalence of antibody studies should show an increasing percentage of people with the antibodies.  The bets have to do with how much increase we will see.  Will NY go from 13% to 26% or higher?  The experience in nursing homes and the disaster in the Soldier’s Home in Holyoke MA, shows that in a vulnerable group the infection rate can explode — https://www.masslive.com/news/2020/04/coronavirus-at-holyoke-soldiers-home-additional-veteran-dies-infection-remains-stable-over-3-days.html. Out of 210 veterans living there 66 have died of COVID19 and 82 more have been infected (showing the genome), since the first case was discovered 21 March.

Showing the conflicting evidence docs have to deal with all the time — consider the prisoner studies — https://www.reuters.com/article/us-health-coronavirus-prisons-testing-in/in-four-u-s-state-prisons-nearly-3300-inmates-test-positive-for-coronavirus-96-without-symptoms-idUSKCN2270RX.

It isn’t clear which test was being used (viral genome or antibodies to the virus).  But this is a younger and healthier population.  Very surprisingly in four state prison systems — Arkansas, North Carolina, Ohio and Virginia — 96% of 3,277 inmates who tested positive for the coronavirus were asymptomatic.

So if healthy people won’t be made sick, what will happen when restrictions on activity (both personal and business) are lifted as they will be shortly?   You have two conflicting pieces of evidence to help you place your bets.  Fortunately the country has not adopted a one-size-fits-all approach, and lots of different experiments of nature will occur.

New York is the epicenter, with the most cases and very high population density.  Symptomatic cases appear to have stabilized even with a 10fold higher transmission rate (as measured by antibody prevalence) than that measured by finding the viral genome itself.

What would be your guidance here?

It’s time to pay our respects to Dr. Janeway who first focused on the innate immune system 30 years ago — https://en.wikipedia.org/wiki/Charles_Janeway.  Obviously if we had to wait the week or so for antibodies to develop to fight off infections, we’d all be dead.  The innate immune system is much older evolutionarily than antibodies and starts working immediately.  We are still finding out how complex it is. https://en.wikipedia.org/wiki/Innate_immune_system.

Like everything else, the innate immune system weakens with age, possibly explaining the difference in clinical outcome between the vets at the Soldier’s home and the prison inmates.

It’s hard to place a bet when you’re wishing for the best possible outcome as are most of us. Some people are highly invested in the worst possible scenarios, particularly those who’ve predicted them.  My guess is that we won’t see a surge in fatal or symptomatic cases as things open up.  What’s yours?

Addendum 27 April ’20.  People who have predicted terrible things happening by opening up some of the restrictions have their egos and reputations involved if they are proved wrong.  So beware breathless reports of spikes in incidence, hospitalization, deaths occurring in the first few days after the restrictions are lifted.  Remember the mean incubation period is 5 days with a range of up to 11 days. 

A bombshell that wasn’t

Yesterday, a friend sent me the following

” Chinese Coronavirus Is a Man Made Virus According to Luc Montagnier the Man Who Discovered HIV

Contrary to the narrative that is being pushed by the mainstream that the COVID 19 virus was the result of a natural mutation and that it was transmitted to humans from bats via pangolins, Dr Luc Montagnier the man who discovered the HIV virus back in 1983 disagrees and is saying that the virus was man made.”

Pretty impressive isn’t it?  Montagnier says that in the 30,000 nucleotide sequence of the new coronovirus SARS-CoV-2 he found sequences of the AIDS virus (HIV1).  Worse, the biolab in Wuhan was working both on HIV1 and coronaviruses.  It seems remote that a human could have been simultaneously infected with both, but these things happen all the time in the lab, intentionally or not.

It really wouldn’t take much to prove Montagnier’s point.  Matching 20 straight nucleotides from HIV1 to the Wuhan coronavirus is duck soup now that we have the sequences of both.  HIV1 has a genome with around 10,000 nucleotides, and the Wuhan coronavirus has a genome of around 30,000.  Recall that each nucleotide can be one of 4 things: A, U, G, C.  In the genome the nucleotides are ordered, and differences in the order mean different things — consider the two words united and untied.

Suppose Montagnier found a 20 nucleotide sequence from HIV1 in the new coronavirus genome. How many possibilities are there for such a sequence?  Well for a 2 nucleotide sequence there are 4 x 4 == 4^2 = 16,  for a 3 nucleotide sequence 4 x 4 x 4 == 4^3 = 64.  So for 20 nucleotides there are 4^20 possible sequences == 1,099,511,622,776 different possibilities.  So out of the HIV1 genome there are 10,000 – 20 such sequences, and in the coronavirus sequence there are 30,000 -20  such sequences so there are 10,000 times 30,000 ways for a 20 nucleotide sequence to match up between the two genomes.  That 300,000,000 ways for a match to occur by chance — or less than .1%.  If you’re unsatisfied with those odds than make the match larger.  25 nucleotides should satisfy the most skeptical.

But there’s a rub — as Carl Sagan has said  “Extraordinary claims require extraordinary evidence.”  Apparently Montagnier hasn’t published the sequence of HIV1 he claims to have found in the coronavirus.   If anyone knows what it is please write a comment.

Then there’s the fact that Montagnier appears to have gone off his rocker. In 2009 he published a  paper (in a journal he apparently built) which concludes that diluted DNA from pathogenic bacterial and viral species is able to emit specific radio waves” and that “these radio waves [are] associated with ‘nanostructures’ in the solution that might be able to recreate the pathogen”.

Sad.  Just as one of the greatest chemists of the 20th century will be remembered for his crackpot ideas about vitamin C (Linus Pauling), Montagnier may be remembered for this.

On second thought, there is no reason to need Montagnier and his putative sequence at all. The sequences of both genomes are known.     Matching any 20 nucleotide sequence from HIV1 to any of the 30,000 – 20 20 nucleotide sequences from the Wuhan flu is a problem right out of Programming 101.  It’s a matter of a few loops, if thens and go to’s.  . If you’re ambitious  you could start with smaller sequences say 5 – 10 nucleotides, find a match, move to the next largest size sequence and repeat until you find the largest contiguous sequence of nucleotides in HIV1 to be found in the coronavirus.

You can read about the Wuhan lab in an article from Nature in 2017 — https://www.nature.com/news/inside-the-chinese-lab-poised-to-study-world-s-most-dangerous-pathogens-1.21487

Do not go gentle into that good night

Cells in the body dying of necroptosis obey Dylan Thomas — “Do not go gentle into that good night” all sorts of inflammation ensues around the cell, and systemically if enough die that way at once.

Cells dying from the first discovered form of programmed cell death e.g. apoptosis disobey.  They die very quietly producing no inflammation, and are quietly munched up by phagocytes.  Just how this happens has been a huge mystery.

Well one way to figure out what is going on looks at a phagocyte before it meets an apoptotic cell and afterwards.  Quite a bit it turns out.  The brute force technique looks at the changes in our 20,000 or so protein coding genes.  They found increased expression in 886 and decreased expression in 966, some 9% of our total.  How do you make sense of that.

This is typical of the brute force approach to any condition (e.g. cancer, infection, vascular disease), and shows you just how hard it is to figure out what is going on from the mass of data produced.

The authors of Nature vol. 580 pp. 130 – 135 ’20 (https://www.nature.com/articles/s41586-020-2121-3.pdf) were far cleverer than that.  What they did was cause a bunch of cells to go apoptotic at once and then the “supernatants and cell pellets from apoptotic cells and live cell controls were subjected to untargeted metabolomic profiling against a library of more than 3,000 biochemical features or compounds.”

Then by a huge amount of work they found 6 metabolites released by the apoptotic cell  which when given together which could switch macrophages (a type of phagocyte)to the non-inflammatory state (e.g. the one above producing all those gene changes).

Then they pared the number of metabolites doing this down to 3 (spermidine, guanosine monophosphate and inosine monophosphate). They call this cocktail of metabolites MEMIX-3.

They get out of the cell dying of apoptosis because the executioner (caspase) chops up a protein channel on the cell surface (pannexin1), allowing the 6 metabolites to escape.  A rather parsimonious suicide note wouldn’t you think.

It gets better. MEMIX-3 obviously is an anti-inflammatory agent, and they showed that it attenuates arthritic symptoms and prevents rejection of a lung transplant.

Brilliant work, and possibly one of great therapeutic import.

Frameshifting

hed oga tet hec atw hoa tet her atw hob ith erp aw

Say what?  It’s a simple sentence made of 3 letter words frameshifted by one

he dog ate the cat who ate the rat who bit her paw

Codons are read as groups of three nucleotides, and frameshifting has always been thought to totally destroy the meaning of a protein, as an entirely different protein is made.

Not so says PNAS vol. 117 pp. 5907 – 5912 ’20. Normally a frameshifted protein has only 7% sequence identity with the original.  This is about what one would expect given that there are 20 amino acids, and chance coincidence would argue for 5%.  But there are more ways for proteins to be similar rather than identical.  One can classify our amino acids in several ways, charged vs. uncharged, aromatic vs. nonaromatic, hydrophilic vs. hydrophobic etc. etc.

The authors looked at 2,900 human proteins, then they frameshifted the original by +1 and compared the hydrophobicity profiles of the two.  Amazingly there was a correlation of .7 between the two, despite sequence identity of 7%.  Similarly frameshifting didn’t disturb the chance of intrinsic disorder.  So frameshifting is embedded in the structure of the universal genetic code, and may have actually contributed to its shaping.  Frameshifting could be an evolutionary mechanism of generating proteins with similar attributes (hydrophobicity, intrinsic order vs. disorder, etc.) but with vastly different sequences.  The evolution, aka natural selection aka deus ex machine aka God could muck about the ready made protein and find something new for it to do.   A remarkable concept.

The gag-pol precursor p180 of the AIDS virus is derived from the gag-pol mRNA by translation involving ribosomal frameshifting within the gag-pol overlap region.  The overlap is 241 nucleotides with pol in the -1 phase with respect to gag (that’s an amazing 80 amino acids).  I was amazed at the efficiency of coding of two different proteins (one and enzyme and one structural), but perhaps they aren’t that different in terms of hydrophobicity (or something else).

I’d love to see the hydropathy profile of the overlap of the two proteins, but I don’t know how to get it.

Decoys and the Strategic Defense Initiative (SDI)

It will take a detour through history to understand how lung cells try to defeat MRSA (Methicillin Resistant Staph. Aureus), a very nasty bug.

Back in 1983 President Reagan proposed building an antiMissile defense system, which would shoot down Russian InterContinental Ballistic Missiles (ICBMs) aimed at us.  Almost every scientist of note said it was impossible technically, because even if you could shoot down one (which they didn’t think you could), the Russians would send multiple decoy ICBMs without warheads.  It was an enormously expensive project and one the Russians had no hope of matching.  People still argue whether their attempt to match the US caused the Russians  to collapse — https://history.howstuffworks.com/history-vs-myth/who-won-cold-war1.htm — although collapse they did being overextended in Afghanistan (as we’ve been for 20 years).

But that’s exactly what A549 cells (derived from lung epithelium) do to fake out MRSA according to Nature vol. 579 pp. 260 – 264 ’20.  One of the reasons MRSA is so nasty is that it secretes a protein (alpha toxin) which forms holes in cells it binds to.  Well alpha toxin has a target it must bind to cause trouble, otherwise it would form holes in everything including itself.  The target is an enzyme on the surface of the cell called ADAM10, which is a protease found on the cell membrane.

You may not have thought of it, but when you diet, your cells eat themselves, rather than just sloughing of the cells in the fat you don’t like (love handles, double chin etc. etc.).  Wouldn’t that be nice though.  The process is called autophagy, in which membranes appear, surround small bits of each cell and them fuse with the lysosome, which breaks the contents down into metabolically useful material (sugars, fats, amino acids).  Some 41 different proteins are involved called ATG’s (for AuTophagy Gene).

But the autophagy genes can also be used to secrete stuff to the outside of the cell, and in fact that’s how the lung cells beat MRSA, they secrete zillions of little vesicles called exosomes (an entirely interesting newly discovered story, to be covered at another time), containing the target of alpha toxin — ADAM10.  Clever no?  The authors were so excited they invented a new word for it the defensosome. The ATG involved is called ATG16L1.  Previously the function of ATG16L1 appeared well defined, conjugating phosphatidylethanolamine to LC3, a ubiquitinLike molecule to form the autophagosome.  That’s probably nomenclature overload, but it’s worthwhile getting an appreciation of the complicated things going on inside our cells.

 

Do orphan G Protein Coupled Receptors self stimulate?

Self-stimulation is frowned on in the Bible — Genesis 38:8-10, but one important G Protein Coupled Receptor (GPCR) may actually do it.  At least 1/3 of the drugs in clinical use manipulate GPCRs, and we have lots of them (at least 826/20,000 protein coding genes according to PNAS 115 p. 12733 ’18).  However only 360 or so are not involved in smell, and in one third of them  we have no idea what the natural ligand for them actually is (Cell vol. 177 p. 1933 ’19).  These are the orphan GPCRs, and they make a juicy target for drug discovery (if only  we knew what they did)

One orphan GPCR goes by the name of GPR52. It is found on neurons carrying the D2 dopamine receptor.  GPR52 binds to G(s) family of G proteins stimulating the production of CAMP (which would antagonize dopamine signaling), enough to stimulate (if not self-stimulate) any neuropharmacologist.

Which brings us to the peculiar behavior of GPR52 as shown by Nature vol. 579 pp. 142 – 147 ’20.  The second extracellular loop (ECL2) folds into what would normally be the binding site for an exogenous ligand (the orthosteric site).  Well, it could be protecting the site from inappropriate ligands.  But it isn’t, as removing or mutating ECL2 decreases the activity of GPR52 (e.g. less CAMP is produced).  Pharmacologists have produced a synthetic GPR52 agonist (called c17).  However it binds to a side pocket, in the 7 transmembrane region of the GCPR.   This is interesting in itself, as no such site is known in any of the other GPCRs studied.

Most GPCRs have some basal (constitutive) activity where they spontaneously couple to their G proteins, but the constitutive activity of GPR52 is quite high, so c17 only slightly increases the rise in CAMP that GPR52 normally produces.

This might be an explanation for other orphan GPCRs — like a hermaphrodite they could be self-fertilizing.

How can it be like that?

The following quote is from an old book on LISP programming (Let’s Talk LISP) by Laurent Siklossy.“Remember, if you don’t understand it right away, don’t worry. You never learn anything, you only get used to it.”

Unlike quantum mechanics, where Feynman warned never to ask ‘how can it be like that’, those of us in any area of biology should always  be asking ourselves that question.  Despite studying the brain and its neurons for years and years and years, here’s a question I should have asked myself (but didn’t, and as far as I can tell no one has until this paper [ Proc. Natl. Acad. Sci. vol. 117 pp. 4368 – 4374 ’20 ] ).

It’s a simple enough question.  How does a neuron know what receptor to put at a given synapse, given that all neurons in the CNS have both excitatory and inhibitory synapses on them. Had you ever thought about that?  I hadn’t.

Remember many synapses are far away from the cell body.  Putting a GABA receptor at a glutamic acid synapse would be less than useful.

The paper used a rather bizarre system to at least try to answer the question.  Vertebrate muscle cells respond to acetyl choline.  The authors bathed embryonic skeletal muscle cells (before innervation) with glutamic acid, and sure enough glutamic acid receptors appeared.

There’s a lot in the paper about transcription factors and mechanism, which is probably irrelevant to the CNS (muscle nuclei underly the neuromuscular junction).   Even if you send receptors for many different neurotransmitters everywhere in a neuron, how is the correct one inserted and the rest not at a given synapse.

I’d never thought of this.  Had you?

 

Amyloid

Amyloid goes way back, and scientific writing about has had various zigs and zags starting with Virchow (1821 – 1902) who named it because he thought it was made out of sugar.  For a long time it was defined by the way it looks under the microscope being birefringent when stained with Congo red (which came out 100 years ago,  long before we knew much about protein structure (Pauling didn’t propose the alpha helix until 1951).

Birefringence itself is interesting.  Light moves at different speeds as it moves through materials — which is why your legs look funny when you stand in shallow water.  This is called the refractive index.   Birefringent materials have two different refractive indexes depending on the orientation (polarization) of the light looking at it.  So when amyloid present in fixed tissue on a slide, you see beautiful colors — for pictures and much more please see — https://onlinelibrary.wiley.com/doi/full/10.1111/iep.12330

So there has been a lot of confusion about what amyloid is and isn’t and even the exemplary Derek Lowe got it wrong in a recent post of his

“It needs to be noted that tau is not amyloid, and the TauRx’s drug has failed in the clinic in an Alzheimer’s trial.”

But Tau fibrils are amyloid, and prions are amyloid and the Lewy body is made of amyloid too, if you subscribe to the current definition of amyloid as something that shows a cross-beta pattern on Xray diffraction — https://www.researchgate.net/figure/Schematic-representation-of-the-cross-b-X-ray-diffraction-pattern-typically-produced-by_fig3_293484229.

Take about 500 dishes and stack them on top of each other and that’s the rough dimension of an amyloid fibril.  Each dish is made of a beta sheet.  Xray diffraction was used to characterize amyloid because no one could dissolve it, and study it by Xray crystallography.

Now that we have cryoEM, we’re learning much more.  I have , gone on and on about how miraculous it is that proteins have one or a few shapes — https://luysii.wordpress.com/2010/08/04/why-should-a-protein-have-just-one-shape-or-any-shape-for-that-matter/

So prion strains and the fact that alpha-synuclein amyloid aggregates produce different clinical disease despite having the same amino acid sequence was no surprise to me.

But it gets better.  The prion strains etc. etc may not be due to different structure but different decorations of the same structure by protein modifications.

The same is true for the different diseases that tau amyloid fibrils produce — never mind that they’ve been called neurofibrillary tangles and not amyloid, they have the same cross-beta structure.

A great paper [ Cell vol. 180 pp. 633 – 644 ’20 ] shows how different the tau protofilament from one disease (corticobasal degeneration) is from another (Alzheimer’s disease).  Figure three shows the side chain as it meanders around forming one ‘dish’ in the model above.  The meander is quite different in corticobasal degeneration (CBD) and Alzheimers.

It’s all the stuff tacked on. Tau is modified on its lysines (some 15% of all amino acids in the beta sheet forming part) by ubiquitination, acetylation and trimethylation, and by phosphorylation on serine.

Figure 3 is worth more of a look because it shows how different the post-translational modifications are of the same amino acid stretch of the tau protein in the Alzheimer’s and CBD.  Why has this not been seen before — because the amyloid was treated with pronase and other enzymes to get better pictures on cryoEM.  Isn’t that amazing.  Someone is probably looking to see if this explains prion strains.

The question arises — is the chain structure in space different because of the modifications, or are the modifications there because the chain structure in space is different.  This could go either way we have 500+ enzymes (protein kinases) putting phosphate on serine and/or threonine, each looking at a particular protein conformation around the two so they don’t phosphorylate everything — ditto for the enzymes that put ubiquitin on proteins.

Fascinating times.  Imagine something as simple as pronase hiding all this beautiful structure.

 

 

When is the AIDs virus really dead?

When should we regard an AIDs virus lurking in the genome of a white blood cell as dead (or at least harmless).  Such proviruses are called defective, and commonly formed, because the process of reverse transcription (of RNA into DNA) is quite error prone.

Most would say an HIV1 provirus in the genome is dead  if can’t reproduce and get outside the cell carrying it.  Not so fast says Proc. Natl. Acad. Sci. vol. 117 pp. 3704 – 3710 ’20.  They show that such defective proviruses can be transcribed into RNA and these RNAs can produce proteins (when translated).

There is some evidence for this as the Nef protein of HIV1 can be detected in cells and plasma even when HAART (Highly Active Anti Retroviral Therapy) has knocked plasma viremia down to a level of under   50 copies/milliLiter.

How could this cause trouble ? Easy.  This would be chronically stimulating the immune system and in effect wearing it out.

This is very new stuff, and the fate of white cells containing replication incompetent proviruses which are still producing proteins isn’t known (but I’m sure this isn’t far off).