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.

Follow us on social media and never miss an article:

Golden Medicine: Use of Plasmons for Cancer Therapy

Cancer is an immensely complex disease to treat. The number of mutations and combinations of mutations that can lead to its development make each “cure” more of a patch to a few specific cases. Couple that with the increasing rate of mutation within cancer cells, and it becomes difficult to even diagnose the issue. Plasmon therapy offers the potential for a broadly applicable treatment, and because it couples well with the bodies immune response, offers a therapy that could decrease the chance for metastatic tumor development.

Before we discuss this topic with greater specificity, a few terms should be defined. Plasmons, from the word plasma, are a material that has electrons that flow back and forth in a wave when light shines on them. Plasmas are just gaseous ions, like lightning or neon signs, and in the case of a plasmon, this plasma is confined to the surface of a nanoparticle. You can read more about plasmon theory here.

Nanoparticles abound in modern technologies and are defined by one dimension, the so called “critical dimension”, which is around two hundred nanometers. For reference, that’s roughly one hundred thousand times smaller than a human hair. This size can afford a variety of unique properties to a molecule: distinct colors, uncharacteristic electronic activities, and even the ability to move through a cellular membrane. All these attributes will come into play in how these molecules interact with cancer cells, so they’re important to keep in mind.  Plasmons are nanoparticles that are so small, that the plasma on the surface can be manipulated by light. This rapid movement of plasma gives rise to heat as it collides with surface particles just as your hands generate heat rubbing together. The type of light that does this can be visible or even radio waves, meaning that very low-energy and harmless beams can be used to generate this rapid heat.

The second bit of background knowledge necessary for this discussion is: how is cancer treated in the first place? Many current cancer therapies come from small molecules roughly the size of glucose. Whether they use metals or strictly carbon, small molecule cancer therapies usually rely on interrupting one or a few cellular pathways, like DNA replication or a checkpoint before mitosis (cell splitting). One of the first nanoparticles approved for cancer therapy have been gold nanorods, which are thousands of times larger than a small molecule and have used physical rather than chemical mechanisms for therapy. To clarify, instead of changing some pathway in a cell, these nanorods can selectively heat cancer cells until the cell dies. If you were to think about this in terms of pest control, nanoparticle therapy is like burning a nest of cockroaches. In that same case, using small molecules like cisplatin would be like spraying the cockroaches with the latest bugkiller.

Extending this analogy, it’s fairly obvious that setting a fire inside someone’s body is not a good medicinal practice, so it would be fair to question how plasmon therapy might be helpful. There are two strategies for plasmon cancer therapy: precision lasers and radio waves which can pass through a body. The earliest use of plasmon cancer therapy used a fiber optic that was inserted under the skin to a location near the tumor. Then, beams of light would hit only the tumor. This has the advantage of targeted dosing, but can still be considered fairly invasive. Others have begun using plasmons that generate that intense heat with radio waves so that no procedure is necessary: simply an injection or ingestion of nanoparticles and then stepping into a radio transmitter This can be impractical if the tumor is not in a confined space. Common gold plasmonic nanoparticles would go inside all cells so healthy cells would be damaged just as easily as cancerous ones. Recent work shows that the surface of the nanoparticle can be changed so that the majority of uptake occurs by cancer cells. Cancer cell metabolism makes the charge of cancer cell membranes different from the charge of normal cell membranes, so these nanoparticles can exploit that difference to target only cancer cells.

With this targeted dosing, plasmons show promise as a noninvasive form of therapy that do not harm the patient and would be applicable to most forms of cancer. Even though the safest and most effective nanoparticles will use gold, treatment costs are currently around  $1000, thereby promising a treatment that will not be prohibitively expensive for the future.

Peer edited by Kasey Skinner.

Follow us on social media and never miss an article:

In Almost Living Color: The First Colored Electron Micrographs of Cells

The electron microscope (EM) was first tested by Max Knoll and Ernst Ruska at the Berlin Technische Hochschule in 1931, remarkably overcoming the resolution limits of visible light for the first time. Modern electron microscopes can magnify objects up to 10 million times their size, and have been used extensively to visualize the inner workings of cells. However, biological imaging by electron microscopy (EM) is usually limited to producing grayscale images since its invention.

https://en.wikipedia.org/wiki/Scanning_electron_microscope

Electron microscopes used to only produce grayscale images.

In the past 15 years, material scientists have developed methods of visualizing colored EM images, but their utility has been limited to imaging synthetic matter. However, a recent study, published in Cell Chemical Biology, has demonstrated a new method to bring super-high resolution colored imaging to the study of biology. The technique uses a special stain made from two rare earth metals, which label the molecules in cells on a microscope slide. When an electron beam is applied to the slide, the majority of electrons pass easily through the sample. However, some electrons that encounter the rare earth metal atoms lose energy, and these low-energy electrons can be detected by a filter on the microscope. Each of the two metals produces a different color. By overlaying the images of the cells before and after labeling, scientists can now create colored images to see details not visible in black and white images.

The study paves the way for scientists to visualize how drugs are delivered to cells, and also how proteins travel within the cell. The developers intend to add additional layers of metals, enabling the colorization of more molecules. By increasing the number of detectable colors, this technique could be used to study even more complex biological processes.

Peer edited by Chiungwei Huang.

Follow us on social media and never miss an article:

 

A Future of Building Designer Cells

If you haven’t seen the cinematic masterpiece that is Jurassic Park, drop what you’re doing and go watch it now. Even if you don’t dig dinosaurs, there’s an immaculate scene of an injured, bare-chested Jeff Goldblum, and that alone is worth your 2 hours and 7 minutes.

Adapted from Jurassic Park

Forget dinosaurs, we need some clones of this guy.

Lusting for a young Jeff Goldblum aside, one thing that resonates scientifically in Jurassic Park, is the ability to piece together bits of prehistoric DNA with frog DNA in order to recreate dinosaurs. It turns out that we’re not too far off from technology like this due to research of several scientists, namely  Dr. J. Craig Venter and Dr. Chris Voigt, in addition to the Human Genome Project-Write (HGP-Write). Continue reading