It helps to be flexible: disordered proteins in biological stress response

Imagine you are working on a project with a large group of people, all with different personalities and responsibilities. Your group was just informed that something important to the progress of the project went terribly wrong. Some people in the group start to panic, which causes other people to panic. There is no defined leader for this group project but you tend to take the lead during stressful times, so you quickly step up to the plate. You know that to get this project back on track, you first need to calm everyone down so that they can refocus on the tasks at hand.

Now try to imagine that instead of people, you and your group are large molecules composed of long chains of amino acids, a.k.a. proteins, and the group project is maintaining the life of your cell.

Much like a dollar bill must undergo many intricate folds to become an origami elephant, chains of amino acids must go through several steps to form a well-folded protein. Top image created by Chris Pielak

Proteins make up many important biological structures (such as hair, nails, and connective tissues) and carry out most chemical reactions in cells (such as converting food into energy or light into sight). For a long time it was thought  that proteins only function once they have “folded” into a highly-ordered shape, similar to how a flat sheet of paper folds into a smile-inducing origami elephant. The unique shape of a protein is dictated by chemical interactions between the amino acids that make up the protein as well as interactions between the protein and water. When drastic changes take place in the environment of the protein (i.e. during cellular stresses such as extreme heat, dehydration, or acidification), these important interactions are disrupted, which can cause proteins that are usually well-folded to temporarily unfold and become inactive. If such a protein remains unfolded for too long, temporary inactivity can become permanent as the protein becomes tangled up with other unfolded proteins in a process known as irreversible aggregation. Under extremely stressful conditions, a significant portion of the proteins in a cell can unfold and irreversibly aggregate, ultimately leading to cell death. So let’s keep all our proteins nicely folded, shall we?

Not so fast! In the past twenty years, the idea that a protein must be folded to function has been challenged by an up-and-coming group of proteins known as intrinsically disordered proteins (IDPs). As the name suggests, IDPs are defined by a distinct lack of a stable, well-folded structure, much like a single strand of spaghetti in a pot of water.

This cat knows spaghetti makes you feel better when you’re stressed out.

Interestingly, organisms across all domains of life have been shown to use IDPs to deal with environmental stresses. Many of these stress-response IDPs are “conditionally disordered”, meaning they can transition into or out of a more ordered state in response to an environmental cue. Given that IDPs are used to being in an unfolded-like state, it kind of makes sense that they can “survive” many of the environmental stresses that typically well-folded proteins can’t. But besides persisting through stressful times, how do IDPs help cells survive extreme environmental stresses? One emerging hypothesis is that stress-response IDPs work by morphing into a shape that can stick to partially unfolded proteins before irreversible aggregation can occur, thus making it possible for stress-sensitive proteins to refold after the stress goes away. In support of this idea, recent studies showed that the bacterial acid-sensing protein HdeA becomes disordered in acidic conditions, and it is in this disordered state that it can stick to partially unfolded proteins and prevent aggregation. Similar modes of action have been proposed for IDPs involved in heat- and dehydration-response as well.

So, just like you in the hypothetical scenario described at the beginning of this post, some IDPs keep the group project (the life of the cell) on track by pulling aside the easily stressed out group members (highly-ordered, stress-sensitive proteins) and calming them down a bit so that once the stress has subsided, everyone in the group can refold and get back to work.

Peer edited by Giehae Choi.

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One thought on “It helps to be flexible: disordered proteins in biological stress response

  1. That is FASCINATING!!! Thanks for posting- I’m dying to know more about these IDPs now! It was also a very fun and interesting read- smile-inducing, like an oragami elephant! Your analogy to a group project also made it very easy to understand!

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