Lesson from a Receptor

Over at BioLogos, Dennis Venema writes a very nice summary of recent research that resurrected a likely ancestral protein state.  Here is the meaty portion:

In vertebrates, two hormone – receptor pairs were of interest to the Thornton group: the mineralocorticoid receptor (MR), which binds a steroid hormone called aldosterone, and the glucocorticoid receptor (GR), which binds a second steroid hormone called cortisol (see diagram above). Cortisol can also activate MRs, but an enzyme that breaks down cortisol is present in tissues where MR is used so cortisol cannot accumulate. Aldosterone, on the other hand, cannot activate GR – it is specific to its binding partner MR. Even though these two hormone / receptor pairs regulate different processes in modern organisms, the two receptors are the result of an ancient gene duplication that occurred early in vertebrate evolution, around 450 MYA (million years ago). As time has gone by, the derivatives of the original gene have picked up distinct binding partners and physiological roles. Thornton and colleagues wanted to tease out the details of these important changes.

They started out by determining the ancestral sequence of the original receptor gene, prior to the duplication, and recreating it in the lab. When they tested this lab-designed protein, they found that it, like modern MRs, (but not GR’s)could bind either cortisol or aldosterone indicating that the ancestral protein must have been able to bind both. This result suggested that somewhere along the line the GR lost its ability to bind aldosterone and became specific to cortisol. This is interesting, because at the time the ancestral receptor was present, aldosterone didn’t exist. Aldosterone is a relative newcomer on the scene: it is present only in four-limbed vertebrates (tetrapods), which arose around 390 MYA. So, the ancestral receptor present prior to 450 MYA already had the ability to bind a hormone that wouldn’t evolve for tens of millions of years. Of course, the ancestral receptor “didn’t mind” – it had its own binding partner – a steroid hormone closely related to cortisol and aldosterone. It wasn’t sitting around doing nothing in the meantime.

As I have noted before, Evo-Devo significantly enhances the plausibility of front-loading by more deeply connecting the past to the present (meaning that original designs would remain connected to the future) and showing us that evolution is constrained and, in some way, guided, by the information present in these original states. Consider what biologist Sean Carroll observed:

We now understand that, no, that evolution works with packets of information and uses them in a new and different ways, and new and different combinations, without necessarily having to invent anything fundamentally new, but new combinations.

That evolution works around ancient packets of information and has no need to invent anything fundamentally new is exactly the pattern we would expect from front-loading.

Consider the example Dennis raised.  I would not call it an “example of front-loading,” but it clearly adds to the plausibility of front-loading.  We now have evidence that a receptor protein was able to bind aldosterone 60 million years prior to the appearance of aldosterone.  And this means the affinity for aldosterone was maintained for 60 million years even though there was no selection pressure to specifically maintain aldosterone binding. A designer with an eye to the future can plan around something like this. Now does this mean such affinity was maintained by some supernatural force? No. Proteins often carry out more than one function and two different functions can be bound through a shared structure (see moonlighting proteins).  It points to proteins as amazing design material, perfectly suited to facilitate evolution.  And if we are smart enough to discover this, a truly smart designer could build their designs around this.

What’s more, the appearance of the two receptors from a single receptor that originally had both functions looks like an example of subfunctionalization mediated by gene duplication, which is also something we would expect from front-loading.  It looks like preadaptation, which is also something we would expect from front-loading.  Like I said, evolution is looking more and more like a splendidly smart process that emerges from the composition and architecture of just two cell plans.  There is no need to impose some non-teleological template on it.

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2 responses to “Lesson from a Receptor

  1. Why isn’t this an example of front-loading?

  2. Hi Nullasulus,

    I envision front-loading with the origin of the first cells. For this to be “an example” of front-loading, it would need to be traced back to this point. But as it stands, we’re at about 500 million years ago.

    Yet I am not denying it as an example either. It’s just that I cannot say.

    For me, the real value here is in the “proof of principle.” We now know that a protein’s ability to bind a specific ligand can predate the existence of that ligand by at least 60 million years. That’s the ball to keep your eye on. It clearly adds to the plausibility of front-loading and I predict we’ll see more results like this as ancestral states are resurrected.

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