Adil Agha Khan
Johns Hopkins University Alumnus
and Biotechnology Master’s Student
The cell is indeed a world of its own. Organelles, the organs of the cell, work together in ways so complex they are breathtaking. There are a variety of different organelles to be found in the approximately 37.2 trillion modern-day human cells (Eveleth, 2013). The modern human cell has been evolving and changing since our eukaryotic ancestors showed up around 2 billion or so years ago (Kondo, 2013).
Life itself as we know it on this planet arrived on the scene about 3.8 billion years ago. There is a lot more evolution that has gone on in the making of us than we can “shake a stick at.” Understanding all of it would—well—take about 3.8 billion years or so worth of knowledge. Thus, if a scientist claims to be sure about all aspects of an organelle—like the proteasome—, we should be raising our eyebrows.
The proteasome has been understood by most to be one-dimensional concerning what it does. But not only is this boring; it’s wrong. The proteasome organelle can classically function as a cellular trash collector and a recycler (at least scientists acknowledged it “goes green”). It recognizes dysfunctional proteins which have been marked for destruction with a ubiquitin-molecule tag and degrades them into reusable monomers.
But you can always learn new things. Like just yesterday I found out that candy corn is called as such because when it is stacked, it looks like corn on the cob. There is more to the proteasome than what had been known thanks to new research previously. Let’s now focus on Dr. Kapil Ramachandran and Dr. Seth Margolis.
The former Dr. Ramachandran is a postdoc at Harvard University and the latter, Dr. Margolis. is a former-Harvard postdoc turned primary investigator in biochemical neuroscience at the Johns Hopkins University. They are here to challenge classically-held scientific notions with scientific fact. They are doing the proteasome its due justice, turning the pauper organelle into a prince. But to be fair, we are not talking about just any proteasome. We are talking about what Ramachandran and Margolis call the “nuclear membrane proteasome” or “NMP” (Ramachandran, Margolis, 2017).
This is a proteasome that resides in the membrane of nerve cells. Another group of scientists, Erokhov et al. (2017) describe Ramachandran and Margolis’ discovery as “proteasomes in the mammalian nervous system that directly and rapidly [modulate] neuronal function by degrading intracellular proteins into extracellular peptides that could stimulate neuronal signaling (Erokhov et al., 2017)”. That’s a mouthful. In simpler terms, Ramachandran and Margolis have discovered a proteasome that while functioning in protein recycling creates chemicals that are integral for nerves to communicate between each other. The plot has thickened.
Ramachandran and Margolis(2017) experimented and observed that when they turned off the NMP, nervous signaling was also turned off. Further, when they reintroduced the chemical signal produced by the NMP, nervous signaling was turned back on. Now we are scratching our chins saying, “Hmm…”. If the information is at it seems, then this is about nerves communicating or not communicating. It makes sense that the NMP works differently from the “classical” proteasome because its very structure is different.
Typically, the organelle is known as having a degradative subunit in the middle sandwiched by two regulatory caps on either end which regulate the entry of the proteins tagged with the ubiquitin molecule as mentioned earlier. The NMP, though—ever the “black sheep of the family”—has a markedly different structure. It has only two of the three subunits, lacking the caps. Imagine a carb-free burger (no buns). The NMP is not your grandfather’s proteasome.
Understanding the NMP could mean understanding the difference between a neuron firing or not firing. Another metaphor is appreciating the difference between a leg moving when a rubber hammer taps a knee or not tapping a knee. Observing differences between an eye blinking or not helps to illustrate the differences in brain signals or not. Understanding proteasome complexes that modulate neuronal function is an area that demands further investigation.
Evelth, R. (2013). Smart News. Retrieved from https://www.smithsonianmag.com/smart-news/there-are-372-trillion-cells-in-your-body-4941473/
Erokhov, Pavel A., et al.(2017). “Detection of active proteasome structures in brain extracts: proteasome features of August rat brain with violations in monoamine metabolism.”Oncotarget, Aug. 2017, https:// www.-ncbi-nlm-nigov.ezp.welch.jhmi.edu/pmc/articles/PMC5642609.
Kondo,B. (2013). Powerpoint Lecture. “Evolution of the Cell.” Slide 27. Advanced Cell Biology I.
Ramachandran, K V, and S S Margolis. (2017).“A mammalian nervous-System-Specific plasma membrane proteasome complex that modulates neuronal function.” Nature structural and molecular biology., U.S. National Library of Medicine, Apr. 2017, https:// www.ncbi.nlm.nih.gov/pubmed/28287632.
Photo Credit: http://www.bostonbiochem.com/products/proteasome