A team of researchers at the University of Massachusetts Amherst has announced major advances in understanding how our genetic information ultimately translates into functional proteins – one of the building blocks of human life. The study, recently published in the Proceedings of the National Academy of Sciences, explains how chaperones display “selective promiscuity” for the specific proteins – their “clients” – that they serve. This property enables them to play an essential role in maintaining healthy cells and is a step forward in understanding the origins of a host human disease, from cancer to ALS.
There are four “letters” in the linear DNA code: A, C, G and T. Due to the complex processes of transcription, followed by protein synthesis and eventual protein folding, these four, two-dimensional letters change into a 20-letter , three-dimensional recipe for proteins. Most of the time, this process works flawlessly, and our cells can build and reproduce themselves smoothly. But if something goes wrong, the results can be catastrophic. Fortunately, cells rely on strict quality control to compensate for the devastating consequences.
The egg-folding process, in which a chain of amino acids takes the definitive form as a protein, can be particularly difficult. Researchers have long known that special molecules called chaperones help harden the protein in its definitive, proper form. These “chaperones” can figure out which proteins are at risk of being deformed and can then lend that protein extra help. But how exactly they do their job is poorly understood: “The chaperones do some kind of magic,” says Alexandra Pozhidaeva, co-editor of the newspaper that contributed to this study as a postdoctoral researcher at UMass Amherst and is currently a postdoctoral fellow at UConn Health. “What we have done is reveal the mechanics behind the trick.”
The trick is that although there are tens of thousands of different proteins in our cells, each with a different shape and function, there are far fewer chaperones. “How is it,” asks Lila Gierasch, senior professor of biochemistry and molecular biology at UMass Amherst and the newspaper’s senior author, “that the same chaperones can help many different proteins?” The answer lies in what the authors call the ‘selective promiscuity’ of the chaperones.
The team relied on the latest, in-house resources from UMass Amherst’s Institute for Applied Life Sciences for a new combination of x-ray crystallography, which provides an incredibly detailed yet static snapshot of the chaperone’s interaction with its protein client yields, and nuclear magnetic resonance, which can establish a fuller, more dynamic picture of this complex process. The team focused its efforts on a specific chaperone family known as the Hsp70s. Hsp70s, according to co-lead author Rachel Jensen, a UMass undergraduate at the time she did this research and now a graduate student at Berkeley, are among the key chaperones because “they play a wide range of critical roles within the cell and help perform many crucial cellular functions. “
While previous researchers artificially used shortened protein chains, the team used much longer chains to study how Hsp70 interacts with its clients. “We have studied a much more complex system,” says Eugenia Clerico, co-lead author and research professor of biochemistry and molecular biology at UMass. “We could study in the laboratory something that mimics what happens in our bodies.”
What they have discovered is that Hsp70s are both promiscuous – they can serve many different proteins – but also selective: the range of proteins they can work with is limited. Additionally, Hsp70s “read” ambidextrously: they can identify which protein chains help by reading their sequences from left to right, as well as right to left.
This breakthrough is not only an advancement in our understanding of how cells stay healthy, it has applications in the real world. “Hsp70s,” says Gierasch, “are involved in so many pathological diseases, from cancer to Alzheimer’s, and host Hsp70s are exploited by parasites and viruses. Understanding how Hsp70s work can help us develop therapeutic strategies against these terrible diseases.”
Reference: Clerico EM, Pozhidaeva AK, Jansen RM, Özden C, Tilitsky JM, Gierasch LM. Selective promiscuity in the binding of E. coli Hsp70 to an unfolded protein. PNAS. 2021; 118 (41). doi: 10.1073 / pnas.2016962118
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