Holding onto the Edge: A New Look at How a SOMAmer Binds

Holding onto the Edge: A New Look at How a SOMAmer Binds

A few fingers there, a couple more fingers over there and a couple well placed feet are all that separate rock climbers from the canyon floor hundreds of feet below. With the ease and grace of spiders, the experienced climbers maneuver quickly over the nearly smooth vertical rock face. What supernatural power do they have that keeps them from succumbing to gravity’s will? None. The climbers have instead developed the muscular strength, the know-how to maximize their grip and a few other handy tools to make the daunting feat easier.

SOMAmers are the elite rock climbers of the aptamer* world. They bear a set of “tools” that give them the advantage of gripping onto proteins in ways that other aptamers cannot. These tools include specialized chemical groups that provide the extra “sticky” factor necessary for SOMAmers to find new holds on their targeted proteins and latch on for an incredibly long period of time.

In recent years, a few papers have detailed how SOMAmers put these tools to work. A new discovery from Dr. Anna Marie Pyle’s lab at Yale University (in a collaboration with SomaLogic) has expanded our insight into how these super-aptamer rock climbers hold onto the rocky outcrops of proteins. They revealed the three-dimensional structure of a SOMAmer bound to interleukin 1α (IL-1α), a very difficult protein to bind with a traditional aptamer (Ren, Gelinas, von Carlowitz, Janjic, & Pyle, 2017). This detailed look at how the SOMAmer interacts with IL-1α revealed not only unique SOMAmer attributes, but also a view of IL-1α that had never been seen.

The structure of the IL-1α binder is truly unique, bearing little resemblance to anything that one might expect when told a SOMAmer is made from mostly DNA. The tiny SOMAmer looks like a ladder thrown off the side of a mountain and trampled by a herd of elephants. This contorted shape is thanks in part to the “tools” the SOMAmer possesses. Unlike other structures of SOMAmers in the literature, this one uses a fancy chemical attachment called “2Naphthyl” (Ren et al., 2017). In the structure, these 2Naphthyl tools form a building block (seen in other SOMAmer structures that use different “tools”) reminiscent of a miniature “zipper” that helps maintain the unusual bent shape (Ren et al., 2017). Aside from the little zipper, what’s really neat about this structure is its unexpectedness in this kind of molecule. It is a new take on “G-quadruplexes (Ren et al., 2017),” which are found throughout nature.

Given this unique and tortuous configuration, how does the SOMAmer hold onto its protein partner? Well, it turns out that the bent ladder structure created a “hand,” with the 2Naphthyl groups forming a sticky pocket in the palm of the hand that provided the bulk of the interaction’s strength (Ren et al., 2017). Additional contacts were made between negatively charged and positively charged atoms in the “fingers” (Ren et al., 2017).

As mentioned above, this unusual structure reveals a lot about the protein as well. Up until now, the research community was aware of the general structure of IL-1α, but knew none of the fine details (Ren et al., 2017). The inclusion of the SOMAmer hand in visualizing the structure helped pull the protein together to form an exquisite crystal that revealed the missing fine details. The research community now sees the elusive sidechains of IL-1α, which in turn illuminate the biology of inflammation and cancer development (Ren et al., 2017). As an extra bonus, the little SOMAmer could also inhibit the protein’s normal function; thus, making it a potential therapeutic for future development (Ren et al., 2017).

With a few tools and the ability to adopt contorted shapes, this tiny hand-like SOMAmer and others can tackle the most difficult of proteins and find great places to hold on. This sticky grip makes it possible to reach new vantage points not achievable by other types of technology. What can be seen from these lofty vantage points? Akin to the beautiful vistas bestowed to rock climbers, we will be able to gaze at never-before-seen vistas of our health.

*(a string of nucleic acids designed to bind to stuff)

References

 

Ren, X., Gelinas, A. D., von Carlowitz, I., Janjic, N., & Pyle, A. M. (2017). Structural basis for IL-1alpha recognition by a modified DNA aptamer that specifically inhibits IL-1alpha signaling. Nat Commun, 8(1), 810. doi:10.1038/s41467-017-00864-2

Take my Breath Away: Diagnosing Asthma’s Severity When Every Minute Counts

Take my Breath Away: Diagnosing Asthma’s Severity When Every Minute Counts

When I first came to the Colorado, the mountains captivated me. They looked so imposing, yet enchantingly beautiful at the same time. A few months later, some of my mountaineering friends convinced me to climb one of these enchantresses (known locally as “14’ers”). They picked an “easy” one because I had spent all my life at a few hundred feet above sea level near the Mississippi River.

We started out on a beautiful crisp fall morning. The sun had yet to rise and illuminate the aspen trees that were already turning a golden yellow. As we climbed higher, the aspen grew smaller and it got colder. As the air grew colder and thinner, I found myself having a difficult time breathing. I kept soldiering on, but the fight for breath was getting harder. According to one friend’s watch, I had made it about 13,700 feet before the struggle for breath grew too much. I had to retreat back to a more oxygen-rich environment. The mountain won this round.

There are individuals who experience the fight for breath every day. The cause of this fight is a condition known as asthma, which can vary greatly in its severity. Diagnosing the severity and determining the correct course of treatment is not always straightforward, quick or cheap (Israel & Reddel, 2017). If new diagnostic tests became available, could they speed up the process of determining asthma severity and thus identifying the best treatment?

An international team of researchers united to answer that very question (Rossios et al., 2017). They queried sputum (another name for phlegm) samples from patients with different degrees of asthma to look for changes in the patients’ transcriptomic (looking at all RNA levels) and proteomic (looking at all protein levels) profiles. The researchers successfully found changes in those profiles that provide new insights about the underpinnings of asthma severity and may even help expedite the diagnosis (Rossios et al., 2017).

These researchers took not just one small step, but one giant leap towards summiting Mt. Improved Diagnostics. Instead of focusing on just one biomarker and looking for its presence in samples provided by patients with different degrees of asthma severity, the researchers utilized technologies that could cast a broad net (Rossios et al., 2017). Using the SOMAscan assay, they could scan various molecular pathways simultaneously, see the differences and achieve a better understanding (Rossios et al., 2017).

The asthma researchers certainly share a great vantage point with others who use proteomics. Proteins, which are the end product of our genes, are responsible for how our bodies respond to the environment, disease, etc. Aside from responding to cues, rogue proteins can also be the cause of disease. By looking at how proteins interact with one another and the downstream effects of those interactions, the scientific community can better discern the onset of disease (Fessenden, 2017). By thinking deeply about the data, it will feasible to scale the enchantress, Mt. Improved Diagnostics, with greater ease and surer breath.

 

References

Fessenden, M. (2017). Protein maps chart the causes of disease. Nature, 549(7671), 293-295. doi:10.1038/549293a

Israel, E. & Reddel, H. K. (2017). Severe and difficult-to-treat asthma in adults. N Engl J Med, 377(10), 965-976. doi:10.1056/NEJMra1608969

Rossios, C., Pavlidis, S., Hoda, U., Kuo, C. H., Wiegman, C., Russell, K., . . . Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes Consortia Project Team. (2017). Sputum transcriptomics reveal upregulation of IL-1 receptor family members in patients with severe asthma. J Allergy Clin Immunol. doi:10.1016/j.jaci.2017.02.045