Construction workers get more respect than cleanup crews, but both are equally important. Imagine if all the debris from building your house never got hauled away. You could probably not walk anywhere without stepping over piles of junk. Cells, too, have masterful architects, busily constructing proteins and other molecules from ingredients imported through the cell membrane. The waste products, though, could quickly crowd out the productive workers. Worse, some of the waste is toxic, requiring specially trained haz-mat teams to deal with it.
Several recent papers show how cleanup crews play essential roles in the cell’s quality control systems. Here’s what three scientists in Germany say about “In vivo aspects of protein folding and quality control” in Science Magazine:
Proteins are synthesized on ribosomes as linear chains of amino acids and must fold into unique three-dimensional structures to fulfill their biological functions. Protein folding is intrinsically error-prone, and how it is accomplished efficiently represents a problem of great biological and medical importance. During folding, the nascent polypeptide must navigate a complex energy landscape. As a result, misfolded molecules may accumulate that expose hydrophobic amino acid residues and thus are in danger of forming potentially toxic aggregates. To ensure efficient folding and prevent aggregation, cells in all domains of life express various classes of proteins called molecular chaperones. These proteins receive the nascent polypeptide chain emerging from the ribosome and guide it along a productive folding pathway. Because proteins are structurally dynamic, constant surveillance of the proteome by an integrated network of chaperones and protein degradation machineries, the proteostasis network (PN), is required to maintain protein homeostasis in a range of external and endogenous stress conditions. [Emphasis added.]
We see here that the cleanup crews work right alongside the construction crews and surveillance crews. “Chaperones are a kind of Technical Inspection Authority for cells,” Phys.org explains. “They are proteins that inspect other proteins for quality defects before they are allowed to leave the cell.” When molecular chaperones cannot fold a protein properly in time, the surveillance crew must make a go/no-go decision, because some amino acids might clump into toxic aggregates. Figures in the Science paper illustrate the “Proteostasis Network” involving cleanup crews like the proteasome system, autophagy, and the lysosome system.
Similar findings were announced in PLOS ONE:
Protein chaperones are molecular machines which function both during homeostasis and stress conditions in all living organisms. Depending on their specific function, molecular chaperones are involved in a plethora of cellular processes by playing key roles in nascent protein chain folding, transport and quality control. Among stress protein families — molecules expressed during adverse conditions, infection, and diseases — chaperones are highly abundant. Their molecular functions range from stabilizing stress-susceptible molecules and membranes to assisting the refolding of stress-damaged proteins, thereby acting as protective barriers against cellular damage.
Another German website describes how the “protein degradation pathway” works to achieve “successful recycling.” Aberrant proteins are tagged with ubiquitin, a small protein, by two independent surveillance crews. A shredding machine called the proteasome recognizes the tags and provides docking points for them. These quality-control measures ensure that only the bad proteins are degraded.
A large number of different proteins in a cell have to be degraded — some 30 percent of all cellular protein structures formed by folding of amino acid chains are faulty. The problem for the cells is that these incorrectly folded proteins do not have a uniform structure, making it difficult to identify all of them correctly. If breakdown of these “useless” proteins goes wrong, they are deposited in the cell and disturb its homeostasis. This can lead to death of the cell and trigger a number of diseases, including neurodegenerative disorders such as Alzheimer’s and Parkinson’s.
It’s been a while since we talked about the proteasome. More has been learned in the past four and a half years. A cell needs just the right number of these trash recyclers. Consequently, their numbers also are regulated for quality control. Nature tells how complicated this molecular machine is.
The proteasome is composed of 33 subunits assembled in two sub-complexes, the 20S core particle (CP), flanked at one or both ends by the 19S regulatory particle (RP) to form the 26S proteasome. Proteasome assembly requires the assistance of proteasome assembly chaperones. Four evolutionarily conserved 19S RACs [regulatory particle assembly chaperones]: Nas2, Nas6, Hsm3 and Rpn14 in yeast, and p27 (also known as PSMD9), p28 (also known as PSMD10), S5b (also known as PSMD5) and Rpn14 (also known as PAAF1) in mammals are needed for regulatory particle assembly. In addition, yeast cells have Adc17, a stress-inducible RAC, which is vital for cells to survive conditions, such as accumulation of misfolded proteins, which overwhelm the proteasome. This suggests that cells have evolved adaptive signalling pathways to adjust proteasome assembly to arising needs, but how this is achieved is unknown.
You get the picture. The proteasome is complex! (We won’t concern ourselves with how cells “have evolved” these systems.)
What happens when the trash system itself gets trashy? Researchers at Massachusetts General Hospital have been figuring out “proteasome dysfunction” and its health consequences. Even little bitty worms in the soil know about how bad that can be. They monitor their trash cans!
Maintaining appropriate levels of proteins within cells largely relies on a cellular component called the proteasome, which degrades unneeded or defective proteins to recycle the components for the eventual assembly of new proteins. Deficient proteasome function can lead to a buildup of unneeded and potentially toxic proteins, so cells usually respond to proteasome dysfunction by increasing production of its component parts. Now two Massachusetts General Hospital (MGH) investigators have identified key molecules in the pathway by which cells in the C. elegans roundworm sense proteasome dysfunction, findings that may have application to treatment of several human diseases.
When the trash system goes wrong, the cell goes wrong. Cancer and neurodegenerative diseases can result.
Autophagy (“self-eating”) is another important cleanup pathway that degrades and recycles waste. It can act on just parts of the cell or the whole cell. Researchers from the University of Missouri found an unexpected place where autophagy plays a vital role. You may have heard that mitochondrial genes are inherited from the mother. After an egg cell is fertilized, the sperm cell’s mitochondria need to be digested to prevent a condition called heteroplasmy. The paper in the Proceedings of the National Academy of Sciences shows how two cleanup crews work together to prevent this condition:
Maternal inheritance of mitochondria and mitochondrial genes is a major developmental paradigm in mammals. Propagation of paternal, sperm-contributed mitochondrial genes, resulting in heteroplasmy, is seldom observed in mammals, due to postfertilization targeting and degradation of sperm mitochondria, referred to as “sperm mitophagy.” Our and others’ recent results suggest that postfertilization sperm mitophagy is mediated by the ubiquitin-proteasome system, the major protein-turnover pathway that degrades proteins and the autophagic pathway…. Our findings provide the mechanisms guiding sperm mitochondrion recognition and disposal during preimplantation embryo development, which prevents a potentially detrimental effect of heteroplasmy.
This brief survey of cell cleanup provides glimpses into a wondrous array of networks of complex molecular machines that know just what to do to keep cells humming. When evolution is mentioned at all, the main thing said is that the machines are “evolutionarily conserved.” In other words, they have not evolved. It’s important that we look at the details inside the cell occasionally. That’s where the evidence for design often shines the brightest.
Photo: Scania front loader via Wikicommons.