Vulnerability to stress - Tet by Tet

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steroid receptors

Ancient protein flexibility may drive ‘new’ functions

A mechanism by which stress hormones inhibit the immune system, which appeared to be relatively new in evolution, may actually be hundreds of millions of years old.

A protein called the glucocorticoid receptor or GR, which responds to the stress hormone cortisol, can take on two different forms to bind DNA: one for activating gene activity, and one for repressing it. In a paper published Dec. 28 in PNAS, scientists show how evolutionary fine-tuning has obscured the origin of GR’s ability to adopt different shapes.

“What this highlights is how proteins that end up evolving new functions had those capacities, because of their flexibility, at the beginning of their evolutionary history,” says lead author Eric Ortlund, PhD, associate professor of biochemistry at Emory University School of Medicine.

GR is part of a family of steroid receptor proteins that control cells’ responses to hormones such as estrogen, testosterone and aldosterone. Our genomes contain separate genes encoding each one. Scientists think that this family evolved by gene duplication, branch by branch, from a single ancestor present in primitive vertebrates. Read more

Posted on by Quinn Eastman in Heart, Immunology Leave a comment

No junk: long RNA mimics DNA, restrains hormone responses

It arises from what scientists previously described as “junk DNA” or “the dark matter of the genome,” but this gene is definitely not junk. The gene Gas5 acts as a brake on steroid hormone receptors, making it a key player in diseases such as hormone-sensitive prostate and breast cancer.

Unlike many genes scientists are familiar with, Gas5 does not encode a protein. It gets transcribed into RNA, like many other genes, but with Gas5 the RNA is what’s important, not the protein. The RNA accumulates in cells subjected to stress and soaks up steroid hormone receptors, preventing them from binding DNA and turning genes on and off.

Emory researchers have obtained a detailed picture of how the Gas5 RNA interacts with steroid hormone receptors. Their findings show how the Gas5 RNA takes the place of DNA, and give hints as to how it evolved.

The results were published Friday in Nature Communications.

Scientists used to think that much of the genome was “fly-over country”: not encoding any protein and not even accessed much by the cell’s gene-reading machinery. Recent studies have revealed that a large part of the genome is copied into lincRNAs (long intergenic noncoding RNAs), of which Gas5 is an example. Read more

Posted on by Quinn Eastman in Cancer, Immunology Leave a comment

Resurrecting an ancient receptor to understand a modern drug

To make progress in structural biology, look millions of years into the past. Emory biochemist Eric Ortlund and his colleagues have been taking the approach of “resurrecting” ancient proteins to get around difficulties in probing their structures.

Steroid receptor evolution

Ortlund’s laboratory recently published a paper in Journal of Biological Chemistry describing the structure of a protein that is supposed to have existed 450 million years ago, in a complex with an anti-inflammatory drug widely used today. MSP graduate student Jeffrey Kohn is the first author.

Mometasone furoate is the active ingredient of drugs used to treat asthma, allergies and skin irritation. It is part of a class of drugs known as glucocorticoids, which can have a host of side effects such as reduced bone density and elevated blood sugar or blood pressure with long-term use.

One reason for these side effects is because the steroid receptor proteins that allow cells to detect and respond to hormones such as estrogen, testosterone, aldosterone and cortisol are all related. Mometasone is a good example of how glucocorticoids cross-react, Ortlund says. That made it an ideal test of the technique of mixing ancient receptors with modern drugs.

“We used this structure to determine why mometasone cross reacts with the progesterone receptor, which regulates fertility, and why it inhibits the mineralocorticoid receptor, which regulates blood pressure,” he says.

Mometasone furoate in complex with the ancient receptor

Scientists have examined the sequences of the genes that encode these proteins at several points on the evolutionary tree, and used the information to reconstruct what the ancestral receptor looked like. This helps solve some problems that biochemists studying these proteins have had to deal with. One of these is: changing one amino acid in the protein sometimes means that the whole protein malfunctions.

“The ancestral receptors are more tolerant to mutation, and they are more promiscuous with respect to activation,” Ortlund says. “That is, they tend to respond to a wider array of endogenous steroid hormones, which makes sense in an evolutionary context. This enhanced activation profile and tolerance to mutation is what we feel makes them ideally suited to structure-function studies.”

The blog Panda’s Thumb has an interesting discussion of this area of research, in relation to the larger question of how proteins evolve.

Posted on by Quinn Eastman in Uncategorized Leave a comment