Ruffling the Feathers of Dinosaurs

The origin of birds remains uncertain, as does the status of feathers on dinosaurs. Review of "Riddle of the Feathered Dragons", by Alan Feduccia. 

As regular readers can surmise, I was raised (scientifically) in an empirical, experimental tradition- that of molecular biology. In that field there is little drama, since any dispute can be taken back to the lab for adjudication. No titanic battles of conflicting interpretations happen, and extremely high standards pervade the field, since any lapse is easily discovered and replicated. Despite the dominant position of molecular biology in the major journals, due to its high productivity, it is thus rarely in the public spotlight. It has been a bit of a culture shock to realize that other areas of science have significantly different standards and epistemology. Many fields (such as astronomy or paleontology) are at heart observational rather than experimental, or have other restrictions or conflicts (medical science, nutrition studies) that impair their ability to find the truth, leading to a great deal more interpretation, drama, and sometimes, rampant speculation.

Paleontology, and the study of the past in general, has an intrinsic lack of data. If the fossils are missing, what can one do but to wonder and speculate what could have happened during that gap? And when fossils do turn up, they still lack alot of information about their unfortunate contributor- they are only the bare bones, after all. They may be in bad condition and particularly hard to interpret. Whole genera or above may be represented by a tooth or single bone. Millions of years may go by with nothing to show for it. No wonder speculation fills the gap- but is that science? Incidentally, I have to thank the Discovery Insitute, with its keen nose for scientific controversy, for pointing me to today's author, who disputes the now-conventional view that birds arose from dinosaurs. While Alan Feduccia has nothing to do with Creationism and its offshoots, and is a perfectly respectable paleontologist, he is, in the course of at least four books on the subject, (of which this is the third), clearly frustrated with the reigning interpretations of his field, which has jumped to what he regards as unwarranted conclusions that have led to a flurry of portrayals of feathered dinosaurs.

The Archaeopteryx fossil, Berlin specimen, which dates to roughly 150 million years ago.

The first bird, more or less, was Archaeopteryx. Its Berlin fossil, found about 1875, and dating to roughly 150 million years ago (mya) is perhaps the most beautiful, and informative, fossil ever found- a complete bird, with fully spread flight feathers on its arms and legs, a long tail, claws on its hands,and teeth in its mouth. It had the precisely the in-between characteristics of both reptiles and birds that gave immediate validation to Charles Darwin's theory of evolution by gradual change and natural selection. But where did it come from? That is the big question. While a great many other fossil birds have been found, none substantially predate Archaeopteryx, (other than perhaps Anchiornis, very similar to Archaeopterix, and dating to roughly 160 mya), and thus we really do not know (as yet) from fossils how birds originated. 

Feathers are one diagnostic feature in this lineage. Archaeopterix and many later birds found in China and Mongolia from the Cretaceous have feathers, clearly marking them as birds and as lineally related. But other allied fossils have been found, nominally described as dinosaurs, which are described to have feathers as well. One is shown below. 

Fossil of Sinosauropteryx, which dates roughly to 124 million years ago.

Closeup of the hair-like impressions on the tail of Sinosauropteryx.

Whether these structures are feathers, or related to them, is quite debatable. They look more like hairs, and Feduccia claims that they do not even occur outside the body wall. Some experimentation by others has shown that sub-dermal collagen can form this kind of hair-like fuzz during some forms of decay and fossilization, given proper squashing. Current conventional wisdom, however, describes them as filament-like feathers used for insulation or display. My take, looking closely at these pictures, is that they are not feathers, but are outside the body wall, which, on the tail certainly, would have been very close to the bone. Additionally, as these specimens are all rather late, they could easily be descended from birds, while being large and flightless. Feduccia points out that while land-based animals have never gained/regained flight, flightlessness has evolved many times through the bird lineages. Similarly, extensive lineages of secondarily flightless birds may have developed in the Mesozoic, that conventional paleontologists call dinosaurs, (often with feathers), and posit as evidence that the reverse happened- that birds evolved from dinosaurs. For example, the conventional view of dinosaurs and birds draws on many later fossils from the Cretaceous (such as Deinonychus), which had both bird-like and dinosaur-like features: the "raptors". 

Another character at issue is flight itself. If birds are basal- that is, they arose prior to or separately from the other dinosaurs- then they could easily have developed from small arboreal lizards that learned to glide from place to place. On the other hand, dinosaurs are all relatively large and bipedal. So conventional paleontologists have labored to come up with ways that flight could have developed "from the ground up". Such theories as insect trapping by nascent small wings, or occasional tree climbing with tiny wings, to escape predators, have been invoked as rationales for feathers and wings to develop in terrestraial bipedal dinosaurs. Feduccia counters that in the whole history of flight, all animals (birds, bats, squirrels, others) have developed flight from gliding, not from the ground up. Indeed, there are countless flightless birds, and none of them have resumed flight, despite presumably having much of the genetic wherewithal to do so.

Given patchy data, the leading method to make sense of it and organize organisms from the fossil record into a phylogenetic story is the cladistic method. Practitioners choose a wide range of "characters", (such as the lengths, angles, holes, and other morphologies in the available bones) and tabluate their values from all the proposed species. Then they can mathematically just total up who is more distant from whom. Feducci emphasizes that this is an excellent method for ordering closely related genera and species. But over the long run, evolution repeats itself alot, making numerous flightless birds, for example, or similarly shaped swimming animals, not all of which are as closely related as they might look morphologically. Cladistics is a classic case of garbage-in-garbage-out analysis, and has routinely been overturned by molecular evidence when, among extant species, genomic data is available. Sadly, genomic data is not available for the fossils from the Mesozoic (the age of the dinosaurs, which encompasses, in order, the Triassic (245 mya to 208 mya), the Jurassic (208 to 144 mya) and the Cretaceous (144 to 65 mya) periods), nor from any living descendants of the dinosaurs... other than their putative decendants, birds.

As an aside, molecular phylogenies are also at heart cladistic in their theory and method. They just have a lot more "characters"- i.e. the letters of the DNA sequences in homologous / aligned sequences. But even more importantly, since a large proportion of these characters are neutral, (to natural selection), and thus vary (in sort-of clock-like fashion) no matter what convergent evolution might happen morphologically, molecular phylogenies can easily resolve difficult questions of phylogeny on the short to medium geologic terms. When it comes to the deepest phylogenies, however, going over a billion years, neutral characters become wholly useless due to homogenization by the vast times that have passed, so for such time periods these methods become less incisive.

Crude cladogram illustrating the alternative hypotheses- that birds are descended from theropod dinosaurs, or that birds arise from a basal lineage of their own, directly from the common stem of archosaurs. In the latter hypothesis, numerous bird-like lineages currently construed as dinosaurs might be secondarily flightless birds.

It is cladistics (along with other evidence) that has enshrined birds within the dinosaur lineage, finding that theropods came first, and the avians came later on. (With a contrasting view, and a critique of the contrasting view.) Theropods and birds are certainly similar, compared to their crocodilian / archosaur antecedents. They are bipedal, with similar hip structures, neck structures, and hands/feet reduced from five to three toes. But if much of what we take to be the dinosaurs (those with feathers and the whole so-called "raptor" class), are actually secondarily flightless birds, then one can make a lot of sense of some of these similarities, while casting the origin of birds quite a bit father back in time, more or less co-incident with the origin of true dinosaurs. Such as in the diagram above.

The problem with all this is again time. The early Jurassic and Triassic, amounting to almost one hundred million years before Archaeopterix, provide a lot of evidence for dinosaurs. They first appear roughly 240 mya, and flourish after the major exinction event that ended the Triassic, at 201 mya. The stark lack of evidence for birds, and widespread evidence for dinosaurs, including the lineage (theropods) that are most related to birds, suggests strongly that birds did not originate back in the Triassic, in parallel with the core dinosaur lineages. It suggests, rather, that among the many theropod dinosaurs during the ten or twenty million years before Archaeopterix were some small enough to take to the trees, grow longer arms, and be in position for flight. There were doubtless plenty of insects up there, at least until just about this time of the late-Jurassic, when birds started to eat them! Fossil record gaps are treacherous things, but this one indicates strongly that birds evolved in the middle Jurassic, along with (and within) the wider adaptive radiation of dinosaurs.

"Yet Archaeopteryx is still the classic urvogel- the oldest well-studied bird yet discovered, perhaps some 25 or more million years older than most of the Early Cretaceous Chinese fossils. As we saw in chapter 3, the Solnhofen urvogel is a mosaic of reptilian and avian features, a true bird, and the more it is studied, the more and more birdlike it is revealed to be. Ignoring the element of geologic time, however, many paleontologists have proposed that the Liaoning fossils provide evidence for all the stages of the evolution not only of birds and bird flight but also of feathers, from fiberlike protofeathers to pennaceous, asymmetrical flight remiges. Such a claim is remarkable and would be astounding in any fauna, but is especially so for a fauna so temporally removed from the time of avian origins, presumably before the Middle Jurassic and perhaps well back into the Triassic. 

University of Pennsylvania paleontologist Peter Dodson, remarking on the inadequacies of cladistic methodology, tells us: 'To maintain that the problem of the origin of birds has been solved when the fossil record of the Middle or Late Jurassic bird ancestors is nearly a complete blank is completely absurd. The contemporary obsession with readily available computer-assisted algorithms that yield seemingly precise results that obviate the need for clear-headed analysis diverts attention away fron the effort that is needed to discover the very fossils that may be the true ancestors of birds. When such fossils are found, will cladistics be able to recognize them? Probably not.'"

Feducci makes a lot of insightful points and hits some sensitive marks, in addition to all the trash-talk. Cladistics has problems, hairs are not feathers, and Cretaceous birds don't tell us much about the evolution of bird flight, which doubtless began as gliding between trees tens of millions of years earlier. And he is right that the hunt for clear antecedents of Archaeopterix, whether far in the past or near, should be the focus of this field. But overall, it is hard to fully credit the "birds early" story. 

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The Impossibility of Morality

We have dark sides and do bad things. How come we all think we are good people?

Part of our political, and temperamental, divide revolves around how seriously to take morality. How idealistic to be about goodness, how hard to try, or whether to be more realistic to be about our dark side. For all the platitudes and commandments, the sad fact is that morality is impossible, so the question is perhaps more how intensively we blind ourselves to darkness rather than how dark we will actually be.

Weird, right? But the closer you look, the more impossible it is to follow any system of morality. There are Jains who will not hurt a fly, let alone eat meat. But plants have feelings too. And our guts contain astronomical numbers of organisms in a roiling dance of macabre death. What about them? Existence as a human is unavoidably destructive. Simpler moral systems preach kindness to others. But again, existence requires feeding one's own fire, and that must come at cost to something, or someone. Every trade is unequal, even if voluntary. Employees are notoriously exploited to give more than their fair share. The Earth is relentlessly exploited. There is no end to our appetites, as long as we are alive.

Psychologically, we build up defenses to say that we are no worse than others, that we are good people. Even if we are bad people, we say that we have been driven to crime, and it is no worse than the rich people who thoughtlessly abuse others. Or if we are a presidential candidate, we say that we are saving the world, and making America great, and the subject of cruel witchhunts. Self-defense is one more essential part of living, even if it comes at the expense of seeing the world clearly. Unflattering visions of our way of life are rejected and repressed, the more so if they come as criticism from others.

Defensive blindness is integral to "modern" life. The agriculture and food processing industry keeps the slaughterhouses hidden, the feedlots and inhumane poultry coops under wraps. The less we know, the better we feel. Money is the ultimate screen against the squeems and qualms of existence, shielding us from the rapacious mining that our electronics drive in tropical forests, the slave labor that makes our clothes, and countless other immoral and destructive processes we are ultimately responsible for. Clear consciousness of all this would make the whole system collapse.

Protesters carrying the pine tree flag of Christian nationalism. While doing good things for the country.

Religions offer their own forms of defense. Confession in the Catholic church is a classic way to touch the darkness, but then to be absolved and feel good again. Exorcisms are offered as well. Protestant approaches tend to focus more on works, like community service, or in fringier precincts, on sermons of self-glorification. Everyone who is reborn in Christ is part of the club, and though a sinner, is also good, glorious, and heaven-bound. Possibly, even, in the Mormon system, himself a god. How they engage with moral darkness varies tremendously by religion, but the common need is to control it, in ourselves and others, sufficiently that our self-image of goodness and light can be preserved.

The extensive repression of moral darkness leads to the countervailing temptation to take another peek at it, under controlled conditions. It is the inspiration for much art- the detective thiller, the horror movie, the general apparatus of drama. Without darkness, there is no interest or light. And people differ markedly in their approach to such material. The more liberal and optimistic tend to focus on the light side, not the dark side, and do so politically as well. They have more moral idealism and hope, which means they have more repression of darker tendencies. Kumbaya is sung. Conversely, the more "realistic", conservative attitude scoffs at the do-gooder idealism of the left, and sees darkness around every corner- in foreigners, in sexual transgression and expression, in fluid social systems, in change itself. They recognize that moral aspiration is futile- such as the woke trend of recent times .. the bending over backwards to every minority group, micro-aggression, every insect and animal, and the climate.. is putting up an impossible and futile bar. That sticking to basics and tradition is going to get us further than such refusal to recognize the dark reality of human existence. 

These valences are apparent in the Palestinian dilemma. As the Palestinians were expelled from Israel during its establishment, the Jews proclaimed a right for Jews all over the world to come to Israel. Meanwhile, the UN created a right of return for Palestinians, to the very same land that formed Israel. It was the ultimate expression of bleeding heart unrealism, and has led (in part) to the existentially stuck misery of Palestinians for all these decades, as the UN took it upon itself to nurture an absurd dream of return and set up a now-permanent refugee apparatus of feeding, schools, and health care, all of which fuels the seething anger and terrorist dreams of ever-growing generations of Palestinians.

Another example is the US war in Vietnam- a curious and tragic mix of blindness, idealism, and realism. We wanted to help the (South) Vietnamese defend themselves from communism. In light of what happened in North Korea in the ensuing decades, this was not a bad goal. North Korea is moral darkness incarnate- a cruel and criminal dictatorship. But once the enormity of the task became clear, the moral realists took charge, with the aim of bombing Vietnam and its neighboring countries into submission. But even such extreme measures failed, leaving us with the ashes of horrible means used in the service of a futile goal. The US media was increasingly unwilling to hide the horrors, bringing into American consciousness all this darkness, which turned out to be unbearable.

So, is it better to blind ourselves to the darkness, and risk destruction and error, or better to be realistic, explore it, even celebrate it, as the Homeric epics do, and gird ourselves to deal with it, and deal it out to others? As in most things, societies are probably best off with a mix of perspectives. This mix is perennially expressed in our political spectrum, though of late the right seems to have gotten caught up in a peculiar reaction against the pieties of the left. As the left has gained the cultural and governmental high ground, as shown by the triumph of gay rights, ever-increasing concern for racial minorities, and a rising tide of official movement on environmental concerns, the right has turned apoplectic. They seem to be saying ... "We love our trucks, we won the continent fair and square, and we won the racial contest as well.."- leave us to our spoils, and don't be so concerned about "fairness" .. life isn't fair or moral, but goes to the darkest, baddest winner. (One can hear echos of the Confederate South in all this clearly enough.) Those on the left who are besotted with woke-ness and fairness will be singing a different tune when they are not at the top of the heap anymore, in their well-gentrified, rich and safe neighborhoods.

Perhaps this portrayal is extreme, but extreme concern for the moral fairness within a society can blind us to other issues, such as the competitive underpinnings of life, both within and verus other societies, and the ultimate impossibility of being totally fair, or moral, as historical actors. A balance of moral idealism and realism about unavoidable dark aspects is needed, but not in a conflict that tears the society apart. That depends on communication between the two sides, and less totalizing certainty from each side's respective mechanisms that repress doubt and screen (or valorize, in extreme cases) various different aspects of darker morality. Religion is notorious for reshaping its adherent's realities and protecting them psychologically from their own evil actions. But left wing certainty functions similarly, with its echo chambers and pieties. So, as usual, deeper insight is needed, mostly of our own blind spots and what they are hiding, but also of how such mechanisms work across the spectrum.

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The Shadow War

We are in a new world-wide cold war. And ironically, the many new technologies from the West have given autocratic states extraordinary new powers. 

Paul Theroux had a remarkable passage in one of his travel books, as he was passing through Myanmar, a military dictatorship then and now, that illuminated attitudes towards China and from China. 

"I heard lots of praise for the United States in distancing itself from the regime, and lots of blame for China and Russia and Singapore in supporting it- China especially. But China's prosperity, its need for oil and wood and food, had created a new dynamic. China had no interest in any country's developing democratic institutions; on the contrary, it was a natural ally of repressive regimes. When the World Bank withheld funds from an African country because it was corrupt and tyrranous, demanding that it hold an election before it could qualify for aid, China would appear with money- 'rogue aid,' with no strings attached, and got the teak, the food, and the drugs." - Ghost Train to the Eastern Star, 2008

The world seems headed into another cold war, definitely rhyming with the last cold war. It is highly unfortunate, and testament to some defects in US management of the post-cold war era, to the surprising durability, even attractiveness, of authoritarian systems, and to the many weaknesses of democratic systems. This new cold war, which I will call the shadow war, features Russia and China as the main poles of opposition to democratic and developed countries, mostly in the West, but including many others. This time around, China is the stronger power by far, and both Russia and especially China are quite advanced in their development, so that the West no longer has a monopoly in any particular technology or kind of organization. China has adopted all the magic of capitalist market mechanisms to grow its wealth, and stolen (or forced the transfer of) huge amounts technology and knowledge to make itself a leader in all sorts of industries.

The West has lately begun to wake up to the problem. Our hope that capitalism was somehow related to, or a leading wedge for, democracy has been dashed several times over. Instead of China turning into Hong Kong, it is Hong Kong that is turning into China. Not only is capitalism, as has been tirelessly pointed out from the left, amoral and indifferent to human rights, (as we already knew from slavery in the US), but democracy is also far more fragile than we had hoped, requiring a wide range of civic understandings, media practices, and forms of education that are far from universal, or natural. We had, in the windup to the cold war, seen many countries make slow and fraught transitions to democracy (Philippines, Taiwan, South Korea, and Eastern Europe), but have more recently seen countries backtrack into autocracy (Russia, Hungary).

Naturally, the war in Ukraine has put the most urgent point on this conflict, where Russia, which is to say its autocratic leader, felt that the existence of an independent and democratic Ukraine next door was too much to bear. Now, China also tells us that it loves its brothers in Taiwan so much that re-unification will come, no matter what the Taiwanese themselves might want. Love certainly takes some strange forms!

But it is a much broader issue, spanning the globe, and the depths of human psychology. On one list of countries ranked by democratic governance, the median country is Armenia, with a "hybrid regime" and scores of roughly five out of ten. This is not a great situation, where half the world, in rough terms, lives in various states of miserable, oppressive government. And as the quote above suggests, the authoritarians have in some ways the stronger hand. What happened?

We in the West had thought that democracy was the natural harbor of all peoples- the end of history, indeed. But in the first place, people power is a very limited power, if whoever has power is authoritarian enough to use tanks against it. And in the second place, democracy is not natural in many cultures. The Muslim culture, for instance, for all its virtues, has a fundamentally patriarchal and tribal governance model, with little room for democracy, though there are, traditionally, various forms of freedom, for men at least. So however attractive democracy is in theoretical terms, and as a model in the West that people from authoritarian countries like to vacation to... as a cultural pattern, it is not universal. And authoritarian patterns are hardly foreign to the West either. The Catholic church is an example of the preserved archetypes of patriarchy and authoritarian strong-man rule.

The Chinese dream is highly militaristic, and rather threatening.

But more deeply, the archetypes we have of leadership and politics are authoritarian.. the king, the hero. Jungian psychology, aside from its focus on archetypes, deals in the shadow, which is our real needs and instincts, insofar as they run counter to our surface goodness and conscious ego construction. A person like Donald Trump exemplifies all these trends. Why on earth are we still saddled with this sociopath after a decade of drama-queenity? He clearly touches a lot of people's archetypal conceptions of strength and heroism. His powers of psychological projection, reflectively rejecting his own shadow, are immense. He is rubber, others are glue. And his fundamental bond with the followers, by licensing their shadow sides of hate and violence, makes his every pronouncement right no matter what. We in the US are facing a cataclysmic political season, trying to repress the shadow of humanity, which is so amply expressed around the world in political / power systems that follow the logic of strength, ending up in states of terror.

Modern technology hasn't helped, either. After a brief flush of excitement about the ability of social media to amplify people power, especially across the Muslim world, it all went to pot as the shallow-ness and disorganization of such movements became apparent. The powers of databases, personal identification, surveillance, and media manipulation have been much more useful to authoritarian governments than to their antagonists, making state terror more effective than ever. Authoritarian countries now control their internet and media environments with great precision, increasingly project their twisted narratives abroad, and even hunt down dissidents outside their borders using the new information tools. So while information may want to be free, it doesn't really have a say in the matter- those with power do.

What to do about it? We in the West have lost control of our media environments. While we are waking up to some extent the the malevalent media from abroad, domestic media is controlled by money, which in the current environment of yawning wealth inequality, political fissiparation, and clickbait "business models" is just as crazy and corrupt. So there should be two approaches to this. One is to strengthen quality media, like PBS and its cohorts, with more offerings and deeper reporting. The other is to restrict how corporations can control media. The right to individual free speech can be preserved while making corporations more sensitive to social goods. The Dominion case against FOX was a small example of the powers available. Liability for lying should be a broader effort in the law, specifically against corporations, which are creatures of the state, not natural persons. We need to recognize the deep psychological powers we are up against in preserving enlightened, respectful civil government and discourse.

Obviously getting our own house in order, against the atavistic forces of political authoritarianism, is the first order of business. Abroad, paradoxically, we need to project strength as a democratic and developed community, holding the line in Ukraine and Taiwan, and against all sorts of authoritarian encroachments, until temperatures are lowered, and the current nationalist fevers abate. For what China has right now is an imperialist fever. It has been weak for so long and surrounded by so many unfriendly countries, that one can understand that it sees its recent economic prosperity as a special opportunity to recover a leading position in its neighborhood, militarily and politically as well as economically. That would be fine if it were not also trying to subvert free political systems and prop up tyrannical ones. There are good reasons why its neighbors are fearful of China.

Like in the last cold war, I think time plays a key role. We have to believe that democracies, for all their weaknesses, are better, and are seen as better, by people around the world. While today's authoritarian powers may have greater durability than those of the communist era due to their embrace of, rather than flouting of, market principles and modern technologies, they are ultimately fragile and subject to the opinions of their own people. Putin will not last forever. Xi will not last for ever. (The Kim regime of North Korea may, however, last forever!) Change is the achilles heal of authoritarian conservatism. So we are in for a very long haul, to keep spreading people power and peace internationally.

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Mopping up Around the Cell

What happens when proteins can't find their partners?

Cells have a lot of garbage disposal issues. There are lysosomes to digest large things like viruses, proteasomes to dispose of individual proteins, and lots of surveillance mechanisms to check that things are going as they should- that proteins coming off the ribosome are complete, that mRNAs are being spliced, that mitochondria are charged up as they should be, that the endoplasmic reticulum is making, folding, and secreting proteins as it should be, among many others. One basic problem that arises when cells have a lot of proteins that assemble and cooperate in the form of complexes, is that some of those subunits may be present in excess, or not join their intended complexes for other reasons such as misfolding. This can have very bad effects. Most protein binding makes use of hydrophobic surfaces, and having these floating around freely can lead to indiscriminate binding / agglomeration, like amyloid plaque formation, and cell death.

Bacteria have one partial solution, which is to encode proteins that are destined to the same complex from the same mRNA, made from what is called an "operon" of genes, like a train with successive gene-carriages. Each multi-protein-encoding message from such an operon is thus necessarily equally abundant, and, assuming simiar ribosomal rates of protein synthesis, the proteins should also be produced in equal quantities, providing at least one method to balance their abundance in the cell. But there are many other issues- proteins may have different life-spans, or different ribosomal production rates, or assembly into the complex may be slow and difficult, so bacteria still are not out of the woods. Eukaryotes do not use operons anyhow, so our more-finely regulated gene control mechanisms are called on to properly equalize (or adjust for) the ultimate subunit concentrations. 

But when all this fails, and there is more of some complex subunit than needed, what happens then? When experimenters over-produce some complex component in cells, it is typically short-lived. And if they impair its production, the rest of the complex tends to be short-lived. This implies mechanisms in the cell to dispose of incomplete complexes and their components. It turns out that there are some specific chaperone proteins that detect such orphan subunits, and tag them to be destroyed. Several prominent complexes, such as ribosomes and proteasomes, even have specifically dedicated mop-up chaperones. A recent paper described a chaperone protein dedicated to mopping up the excess or misfolded subunits of another large and abundant complex - the chaperonin complex. That makes this protein, ZNRD2, a sort of metachaperone.

Some structural (though not dynamic) views of the CCT complex. A shows top and side views, respectively. C shows a layout of how the equator of the complex looks, as coded by each of the subunits. At the ring-ring interfaces are the ATP binding sites (d). And lastly (e) a cut-away view of the inside show where substrate proteins are enclosed and encouraged to fold correctly.

The chaperonin complex, (also called CCT), is a large, hollow sphere that actively helps other proteins to fold correctly. The structural proteins actin and tubulin are the most prominent targets that need this help. When first synthesized, they are bound by adapters that ferry them to the chaperonin complex, which lifts its lid to allow the protein in. Then, ATP is used to induce dramatic cycling of the chaperonin structure, shifting from an internal hydrophobic structure to a more hydrophilic one. This allows the unfolded protein to alternately splay open over the hydrophobic surface, and then fold in piece-wise fashion, for as long as it takes till the barrel detects that it is fully folded and no longer sticking to the hydrophobic internal surfaces.

In the current work, the researchers drove the expression of several individual CCT subunits in cell lysates. Then they sent the products into a mass spectrometer to find out what was sticking to these "orphan" proteins. They found two major associated proteins, HERC2, and ZNRD2. HERC2 is known as a ubiquitin ligase, which is one of a large family of enzymes that tag proteins with ubiquitin, targeting them for disposal. But ZNRD2 was totally uncharacterized, known only as an auto-antigen reacted to by some people with Sjogren's syndrome or scleroderma. The question then was .. does HERC2 directly sense the presence of free-floating CCT subunits, or does it need a helper to do so, such as perhaps ZNRD2?

"... a sizable population of multiple CCT subunits are orphaned even under normal conditions, and the degradation of a subset of these can be stimulated by HERC2."

The researchers showed that deleting HERC2 strongly impaired the cleanup of most orphan CCT subunits. It is evident, however, that there are other chaperones not covered in this work that help clean up some of the other CCT subunits. Then they found that HERC2 interaction with the CCT proteins was dependent on ZNRD2, but that the reverse was not the case- ZNRD2 binds CCT subunits in any case. This, and other experiments, including mapping the location within the HERC2 protein that binds ZNRD2, showed that ZNRD2 is the adapter that does the detailed detection of orphaned CCT subunits. At only 199 amino acids, there is not much to it, and searches for domain signatures do not yield much. Its name reflects a structure that uses zinc ions for stabilization, but much of the protein is also disordered. It is notable for a high proportion of hydrophobic amino acids (alanine, leucine) and lots of prolines (15), which would contribute to a disordered structure. 

Thankfully, with the advent of AI and alpha-fold, these researchers could also investigate and model how ZNRD2 interacts with both the HERC2 ubiquitin ligase and with one of the CCT subunits, CCT4- all without doing any laborious structure determinations.

AI-calculated structures of the complex of the ubiquitin ligase HERC2 with the adaptor ZNRD2 and the target subunit CCT4. At right, the hydrophobic residues of CCT4 are colored yellow, showing that the ZNRD2 orphan subunit detector and adaptor binds to a hydrophobic pocket which would otherwise be completely buried with the full CCT structure. The interacting domain of HERC4 in green is termed a 7-bladed beta propeller.

"In the fully assembled CCT double ring, all potential ZNRD2 interaction sites are completely buried because they form the interface between the two individual rings."

 

They found that ZNRD2 binds to a hydrophobic pocket of CCT4, a pocket that is otherwise buried in the fully assembled CCT. This patch would also be exposed on partially assembled CCT complexes, indicating that this interaction is not only relevant for mopping up the individual subunit, but for several kinds of incomplete assembly of the entire complex, perhaps explaining why other subunits are also mopped up by this system. 

This kind of work is a good example of normal science. A gene about which nothing was previously known (ZNDR2) is now given a function in the cell, and a process circumstantially known to exist is fleshed out with actors and structures that explain it. Of the ~20,000 human protein-coding genes, roughly ten percent still have no annotation, and many more have only tenuous annotation, perhaps only drawn from structural analogy, not direct study. So there is a great deal more work needed to evaluate our parts list, even on the most basic level, even before getting into the complexities of how these proteins act and interact in tissues and pathways. 

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