Skip to Content

The Mystery of Knotted Proteins

Biologists are getting closer to figuring out why nature ties knots in some molecules, which could lead to better drug discovery.

Proteins are long chains of amino acids that are essential building blocks for all living things. These chains form complex three-dimensional shapes that play a key part in their function—when molecules fit together like a lock and key, for example.

So one of the great challenges in molecular biology is to understand how proteins form these shapes, and how they do it so reliably and rapidly. This is the problem of protein folding.

There is an interesting subplot in this mystery. For many years, molecular biologists argued that although proteins can be highly tangled, they could not form knots under ordinary circumstances because this would trap the structure and prevent it from folding further.

Since the turn of the century, however, a different view has emerged. Biologists have discovered that some proteins do form knots. And that raises a couple of interesting questions: how do these knots form and why?

Today, we get an insight thanks to the work of Sophie Jackson at the University of Cambridge and a couple of pals. These guys review the field of knot-forming proteins and set out the major questions that remain unanswered.

This work has significant potential. Proteins that are unfolded or misfolded can have toxic effects, so a better understanding of knots and why they form could have important medical implications.

Knots are usually catalogued in terms of the number of crossings and the number of variations these crossings allow. A simple trefoil knot has three crossings with just one variation, so this is designated 31. The more complex knot with five crossings has two versions designated 51 and 52, while knots with seven crossings come in seven varieties designated 71, 72, … 77. And so on. The number of variations increases exponentially with the crossing number.

Biologists have discovered an increasing variety of knotted proteins. Indeed, about 1 percent of the entries in the Protein Data Bank are knotted, and at least 19 proteins form simple 31 trefoils.

Some of these knotted proteins play an important role in human biochemistry. For example, human ubiquitin C-terminal hydrolase isoform 1 (UCH-L1) is 52 knotted and accounts for up to 5 percent of soluble proteins in neurons.

UCH-L1 has been the focus of considerable study, not least because an unknotted version of this molecule is implicated in Parkinson’s disease. In one study, researchers used optical tweezers to create different versions of this molecule that were either unknotted, 31 knotted, or 52 knotted. They then measured how the protein refolded.

As it turns out, the presence of a knot significantly slows the rate at which a protein folds. It also creates a more complex energy landscape that allows a much wider range of intermediate shapes to form during the folding process. What’s more, the 52 knotted region ends up being much larger than it need be.

Exactly what role the additional shapes might play or why a slower folding speed may be important isn’t clear. All this will need to be explored computationally in the future. The complexity of these problems makes this hard, even for today’s most powerful computers, so better folding simulations will be an important area for future work.

One interesting clue is that knots often occur in proteins near the sites where enzymes bind to the molecule. That suggests that the knot shape forms a crucial part of the lock and key shape. This may explain their presence—knots may allow a protein to form shapes that are otherwise difficult or impossible to achieve.

Jackson and co finish by listing a set of unsolved questions in this field. Some of these are related to limitations in the way biologists can simulate knotting—for example, do these simulations miss any important steps in the knotting process?

Another challenge is to understand whether more complex structures can form out of composite knots, when one knot forms inside another. Some theoretical work suggests that these kinds of structures could have important benefits.

And finally, is it possible to change a knotted protein into an unknotted one with a few judicious cuts in the structure? That’s something that an enterprising enzyme might easily achieve.

A better understanding of the role knots play in protein folding will have important implications for biochemistry. And this kind of knowledge can also be put to good use in discovering and developing therapeutic drugs. That’s why these questions have more than academic interest.

Ref: : How to Fold Intricately: Using Theory And Experiments to Unravel the Properties of Knotted Proteins 

Keep Reading

Most Popular

conceptual illustration of a heart with an arrow going in on one side and a cursor coming out on the other
conceptual illustration of a heart with an arrow going in on one side and a cursor coming out on the other

Forget dating apps: Here’s how the net’s newest matchmakers help you find love

Fed up with apps, people looking for romance are finding inspiration on Twitter, TikTok—and even email newsletters.

computation concept
computation concept

How AI is reinventing what computers are

Three key ways artificial intelligence is changing what it means to compute.

still from Embodied Intelligence video
still from Embodied Intelligence video

These weird virtual creatures evolve their bodies to solve problems

They show how intelligence and body plans are closely linked—and could unlock AI for robots.

We reviewed three at-home covid tests. The results were mixed.

Over-the-counter coronavirus tests are finally available in the US. Some are more accurate and easier to use than others.

Stay connected

Illustration by Rose WongIllustration by Rose Wong

Get the latest updates from
MIT Technology Review

Discover special offers, top stories, upcoming events, and more.

Thank you for submitting your email!

Explore more newsletters

It looks like something went wrong.

We’re having trouble saving your preferences. Try refreshing this page and updating them one more time. If you continue to get this message, reach out to us at with a list of newsletters you’d like to receive.