Protein Pirouettes: Part 2

Amyloid

Welcome to our Protein Pirouettes series! This series is designed to teach you about the wonderful world of proteins, so that you too can learn to dance like a protein. If you haven’t read our introduction- check out the first part of the series here. You can also watch this great video here– for expert level dancing on the smallest possible scale. For more information about the author, check out our about us page.

Hello readers! Cooper here! Welcome back to our Protein Pirouettes series. In the last article, I talked a lot about where proteins come from, why they need to fold, and touched on the elaborate dance of protein folding that proteins must perform to function. In this article, we’ll dive deeper into this process, and explore what happens when it goes horribly wrong. 

When you’re stuck in a rut, just keep dancing.

As proteins twist and turn, they take on different shapes that we call conformations. In search of a functional, highly organized, low entropy shape, proteins sometimes get stuck into non-native conformations (intermediately folded states, or simply called intermediates).2These chaotic, entropy laden states are intermediates on the pathway towards fulfillment of the protein’s purpose. Oh, woe is the protein! But do the little dancers give up? Of course not—they do what they always do. They dance

Protein Chain Diagram
Simplified protein folding funnel, showing a handsomely drawn protein perform the Cha Cha slide. Two hops this time!

 

The protein vibrates with wanton abandon, strands of amino acids bumping into each another recklessly and randomly, trying out new moves. It doesn’t give up. Eventually, something just seems to feel right, the protein settles into its groove and becomes more stable, escaping the rut and dancing towards its goal. When faced with a hurdle in life, consider meeting the challenge like a protein: just keep dancing.

Friends don’t let friends dance alone.

Remember the chaperones at your high school prom? Proteins don’t always get to dance without chaperones either. Sometimes, to dance their way to the next conformation, proteins enlist the help of a chaperone.3Chaperones are protein themselves, and when they see a fellow protein dancing, they get up and dance along with them! Cells are like busy night clubs, and it’s hard to dance when there are innumerable other proteins dancing all around you! Just like our high school prom chaperones, protein chaperones facilitate the party so that nothing too-crazy happens. After all, sometimes dancing doesn’t turn out like it should. 

Amyloid
If you’re an amyloid, you’re going to have a bad time.

Go home amyloid, you’re drunk.

Without the safe watch of a chaperone, proteins may accidentally take on a misfolded conformation that is particularly terrible. These misfolded proteins are like that guy at prom that drinks a little bittoo much of the booze he stole from his parents, and ends up vomiting all over the hardwood dance floor of the gym. Don’t be that guy. Proteins don’t want to be that guy either, and, in the world of proteins, that guy’s name is amyloid.3Amyloids form when misfolded proteins get squished together, and they’re dangerous to your health. For example, plaques of amyloid beta proteins are implicated in the development of Alzheimer’s disease.6So, take a tip from proteins: dance responsibly. 

—Cooper

Notes

  1. Video clip of a protein folding simulation.1
  2. Protein folding funnel drawn in Microsoft Paint. The width of the funnel represent entropy, with decreasing entropy as the funnel narrows. The height of the funnel represents Gibbs free energy, with energy decreasing from top to bottom.2
  3. Adapted, surface structure of a 42-residue beta-amyloid fibril (2MXU) visualized in NGL.4-5

References

  1. Theoretical and Computational Biophysics Group at the NIH Center for Macromolecular Modeling and Bioinformatics. Folding of a Three-helix Bundle Protein. Online video clip. YouTube. 2013. Retrieved from https://www.youtube.com/watch?v=XsQgjxMDjNw.
  2. Wolynes PG, Onuchic JN, Thirumalai D. Navigating the Folding Routes. Science. 1995;267(5204):1619.
  3. Dwevedi A. Protein Folding: Examining the Challenges from Synthesis to Folded Form. SpringerBriefs in Biochemistry and Molecular Biology. 2015. ISBN 978-3-319-12592-3. 
  4. AS Rose, AR Bradley, Y Valasatava, JM Duarte, A Prlić and PW Rose. Web-based molecular graphics for large complexes. ACM Proceedings of the 21st International Conference on Web3D Technology (Web3D ’16): 185-186, 2016. doi:10.1145/2945292.2945324.
  5. AS Rose and PW Hildebrand. NGL Viewer: a web application for molecular visualization. Nucl Acids Res (1 July 2015) 43 (W1): W576-W579 first published online April 29, 2015. doi:10.1093/nar/gkv402.
  6. Aisen PS, Cummings J, Jack Jr. CR, et al. On the path to 2025: understanding the Alzheimer’s disease continuum. Alzheimers Res Ther. 2017;9:60. doi:10.1186/s13195-017-0283-5.

When Pills Weren’t Enough

Pills. Image by qimono on Pixabay.
Pills. Image by qimono on Pixabay.

When I became mysteriously ill in 2016, I learned a crucial lesson: pills were not going to be enough.

Formerly a college student of average health, comfortably floating along on Prozac, Adderall, and birth control, I was shocked when I took a lab job and started experiencing nothing short of bodily retaliation soon after. I developed extreme fatigue, had three heavy periods within two months, and suffered panic and anxiety attacks for the first time.

Desperate to find a quick solution, I visited several different medical professionals. The general practitioner took me off Adderall, switched my antidepressant, and told me to take vitamin D. The gynecologist switched my birth control. The BioTE clinic shoved a testosterone pellet into my hip. The others, well, they gave me advice but couldn’t really help me beyond that.

Despite all the pills and the pellet, my health continued to plummet. Eventually, I had an anxiety attack so bad that I was practically bedridden for a couple of days, and during that time, I made the heartbreaking decision to quit my job. My father agreed to financially support me while I rehabilitated myself, and boy did I have my work cut out for me. After all, I’d just spent months trying to do exactly that, but at that point, it became clear to me that pills were not going to be enough.

I was very weak. My body needed fourteen hours of sleep each day, I was extremely depressed, and my confidence and self-esteem had been shattered. I could hardly do any housework, and I mostly laid on the couch for at least the first month. So I had to start very small.

Thought. Image by TeroVesalainen on Pixabay.

The first treatment I could tolerate was Cognitive Behavioral Therapy (CBT) with a licensed counselor, which I had started a couple months before I quit the lab job. I decided to continue meeting my counselor once per week, uncovering the roots of my mental stigmas, venting to get some of my burden off my heart, and most importantly, rewiring my brain by teaching me to view my problems in a different light. That latter component serves as the key behind CBT. Once I learned to reframe my thoughts, I began to see my life much more positively and regain some of my confidence.

Essential oils. Image by monicore on Pixabay.

The second treatment I added to my regimen was aromatherapy, an Eastern medicine practice in which one inhales purified essential oils as a means of boosting health. While many oils can soothe physical problems like headaches or allergies, I used them for their emotional properties. I quickly discovered two favorites: clary sage and lime oil. Clary sage oil helped me calm down and find mental clarity, and occasionally, it inspired me to be creative. Lime oil gave me a little energy and sharpened my focus. Aromatherapy became a critical component to my recovery by encouraging me to get off the couch and search for my next job.

Healthy food. Image by sansoja on Pixabay.

The next thing I worked on (and continue to improve in my life to this day) was cooking healthier. I finally had enough time to cook meals at home instead of ordering takeout, so immediately the quality of my meals leapt upward. After tracking my meals for at least a week on a few different occasions, I learned where I had deficiencies or excesses in certain nutrients, and I would then adjust my weekly meal plan to accommodate for them. This had the biggest impact on my energy levels and overall wellbeing.

(For healthy meal ideas, check out our Recipes page.)

Yoga. Image by StockSnap on Pixabay.

Lastly, once the first three additions to my life inspired me enough, I tried yoga. I practiced short YouTube routines only lasting about 15-20 minutes, but that small start in regular exercise created a lasting impact on me that developed into me doing weekly cardio, strength training, and stretching. Most immediately, learning to control my breathing and balance reduced my anxiety and depression, making me feel calmer and happier. Later on as I added a variety of exercises to my regimen, I regained my confidence.

Pills. Image from Canva.

All of this is not meant to discredit prescription medications, but rather to emphasize that health is multidimensional, requiring a balance among a wide variety of elements. In my case, I found medications that made me feel somewhat better, but I still needed to improve my diet, exercise regularly, learn healthy coping mechanisms and stress outlets, and reevaluate my career ambitions. Without all of those other things in check, I was weak and unfit to work. Now, I have more confidence and strength than I ever had before.

Pills only make up about half of the health equation, at best. I hope that my experience will encourage you to adopt a more holistic approach with your own health, not just within your body, but with the wide range of treatments and practices available, too!

Protein Pirouettes: Part 1

Ezetimibe

How to Dance Like a Protein: Part 1

Ezetimibe
Pirouettes performed by the target protein of the drug ezetimibe, a medication used to lower cholesterol (a).

Proteins—the practically invisible, molecular dancers that serve as the faithful building blocks of me and you. Yes, it is true that even dancers are made of dancers, and proteins perform some of the most amazing dancing of all by way of folding. Protein folding is actually a lot like belly dancing, with all of its vibrations and shimmying.

Now, I am not—by any leap of the imagination—a dancer, but I do happen to know a lot about nature’s smallest dancers of all. Perhaps you can find some inspiration in learning about our nanoscopic friends, and learn about the science of protein folding along the way!

Butterfly Protein
The humble butterfly protein. Or two chicken legs pressed together? Choose your own adventure (b).

A reason to dance. What, you think that the protein above woke up looking that beautiful? To understand how and why a protein folds, it’s important to remind ourselves of how they come to exist in the first place—the central dogma of molecular biology. DNA is transcribed into mRNA, and mRNA is translated in proteins. That probably sounds like an awful lot of alphabet soup, but let’s simplify things with an analogy: your cell is a small company called Cell Incorporated®. Every company needs a CEO to boss everybody around, and that’s “DNA” (deoxyribonucleic acid), whose office is located in the center (nucleus) of Cell Inc.®. However, even a visionary leader is powerless if they cannot communicate that vision, so they employ messengers called “mRNA” (messenger ribonucleic acid). Now, the company needs to produce something to make a profit, and that product is called “proteins.” Ergo, the central dogma of molecular biology: DNA -> mRNA -> proteins.

To make their product, Cell Inc.® needs raw materials—these are chemicals called amino acids, the steel from which proteins are made. As a protein is being constructed (or translated from the “language” of nucleic acids to amino acids), it is formed piece by piece in a long chain. Imagine that every component that makes up a cell phone was attached to one another by a tiny string; if you laid out that string, it would look nothing like a cell phone (let alone work like one), and the same is true for proteins. Unfortunately for them, cells don’t have the benefit of assembly lines and blue collar workers; therefore, the product must put itself together.

Understand the immense difficulty of this task for a moment: Cell Inc.® needs to make a product out of steel blocks connected by string that, due to the unique properties of each block, will self-assemble into something useful, something beautiful (cell phones are beautiful, okay?).

Wow.

Fortunately for them, however, cells possess the most powerful allies in the entire universe: the laws of physics (c). And it is these laws that govern what is possible, what is probable, and what isn’t. Using physics, Cell Inc.® came up with a solution to make its products self-assemble—to make the pieces of the protein fold nicely together: they dance.

Dancing with purpose. There, I said it: protein folding is dancing. Proteins jiggle, wiggle, twist, and turn, always moving, vibrating, and colliding with themselves and anything else around. Although the motions may be random, the dance itself is done with an immense sense of purpose, guided by the very nature of the protein itself. From chaos and entropy, proteins allow their amino acid bodies to guide their movements towards the native structure, the final, functional form of proteins that we’re familiar with (see the image above). From the very moment that a protein is born, it begins to fold—dancing, you might say, is an integral part of the nature of what it means to be a protein.

There’s an important life lesson to be learned from the humble protein, here. We should allow our natural talents and capabilities to guide our decisions, rather than force upon ourselves choices that deviate from the desires of our hearts. In the early moments of a protein’s birth, it seems impossible to foresee anything of worth or interest arising from a tangled mess of amino acids slapped together, moving erratically in the dark loneliness of a cell. However, perhaps if we live our lives like a protein—following our hearts, listening to our bodies, and maybe even a little dancing—we can find fulfillment, and become the best, most beautiful version of ourselves that we can be.

You do you, aquaporin. You do you (d).

To learn more about proteins, check out my second article here. I’ll be exploring protein folding in greater detail, and discuss how even one false move on the dance floor can transform an otherwise contributing member of cellular society into a murderer.

—Cooper

TL;DR:

  • Proteins are made up of amino acids
  • Central dogma of molecular biology: DNA -> mRNA -> proteins
  • During and after translation, proteins must fold to become functional
  • Protein folding happens as a consequence of the protein’s inherent chemical structure

Notes

(a) Adapted, surface structure of human NPC1L1 (3QNT) visualized in NGL. (1-2)

(b) Adapted, surface structure of human DNA topoisomerase IIa ATPase/ADP (1ZXN) visualized in NGL. (1-2)

(c) This is ultimately where biochemistry comes from; biochemistry is the study of biological chemicals, chemistry is the study of chemicals and how they interact, and those interactions are governed by the law of physics. Biochemistry is basically biological chemical physics. The laws of physics, as they apply to biological chemicals (biochemistry), govern the movements and interactions of proteins (which are also biological chemicals, albeit bigger ones)—just as they govern the movements and interactions of us.

(d) Adapted, surface structure of bioassembled human aquaporin (4CSK) visualized in NGL. (1-2)

References

(1) AS Rose, AR Bradley, Y Valasatava, JM Duarte, A Prlić and PW Rose. Web-based molecular graphics for large complexes. ACM Proceedings of the 21st International Conference on Web3D Technology (Web3D ’16): 185-186, 2016. doi:10.1145/2945292.2945324.

(2) AS Rose and PW Hildebrand. NGL Viewer: a web application for molecular visualization. Nucl Acids Res (1 July 2015) 43 (W1): W576-W579 first published online April 29, 2015. doi:10.1093/nar/gkv402.

Part 2 coming soon!