`Selective promiscuity,' chaperones and the secrets of cellular health
New research reveals how 'molecular chaperone machines' keep our bodies running smoothly

Date:
October 12, 2021
Source:
University of Massachusetts Amherst
Summary:
A team of researchers has announced a major new advance in
understanding how our genetic information eventually translates
into functional proteins -- one of the building blocks of human
life. The research elucidates how chaperones display 'selective
promiscuity' for the specific proteins -- their 'clients' -- 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 of human illnesses, from cancer to ALS.



FULL STORY ==========================================================================
A team of researchers at the University of Massachusetts Amherst has
announced a major new advance in understanding how our genetic information eventually translates into functional proteins -- one of the building
blocks of human life. The research, recently published in the Proceedings
of the National Academy of Sciences (PNAS),elucidates how chaperones
display "selective promiscuity" for the specific proteins -- their
"clients" -- 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 of human illnesses, from cancer to ALS.


========================================================================== There are four "letters" in the linear DNA code: A, C, G and T. Through
the complex processes of transcription, followed by protein synthesis and finally protein folding, those four, two-dimensional letters turn 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 when something goes awry, the results can be catastrophic. Luckily, cells rely on a rigorous quality control to offset
the devastating consequences.

The protein folding process, during which a chain of amino acids assumes
its final shape as a protein, can be especially fraught. Researchers have
long known that special molecules called chaperones help shepherd the
protein into its final, correct shape. These "chaperones" can figure
out which proteins are at risk of being deformed and can then lend
that protein additional help. But how exactly they do their work has
been poorly understood: "The chaperones do some kind of magic," says
Alexandra Pozhidaeva, co-lead author of the paper who contributed to
this study as a postdoctoral research associate at UMass Amherst and is currently a postdoctoral fellow at UConn Health. "What we've done is to
reveal the mechanics behind the trick." The trick is that, though 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, Distinguished Professor of biochemistry
and molecular biology at UMass Amherst and the paper's senior author,
"that the same chaperones can help many different proteins?" The answer
lies in what the authors call the chaperones' "selective promiscuity."
The team relied on the cutting-edge, in-house resources of UMass Amherst's Institute for Applied Life Sciences for a novel combination of x-ray crystallography, which yields an incredibly detailed high-resolution
but static snapshot of the chaperone's interaction with its protein
client, and nuclear magnetic resonance, which can capture a fuller,
more dynamic picture of this complex process. The team focused their
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 conducted this research and now a graduate student at Berkeley,
are among the most important of chaperones because "they carry out a wide
range of critical roles within the cell and help execute many crucial
cellular functions." Whereas previous researchers used artificially
shortened protein chains, the team used much longer chains to study how
Hsp70's interaction with their clients. "We studied a much more complex system," says Eugenia Clerico, co-lead author and research professor of biochemistry and molecular biology at UMass.

"We were able to study in the lab something that mimics what happens in
our bodies." What they discovered is that Hsp70s are both promiscuous
-- they can service 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 to help
by reading their sequences either from left to right, or right to left.

Not only is this breakthrough an advance in our understanding of
how cells stay healthy, it has real-world applications. "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." ========================================================================== Story Source: Materials provided by
University_of_Massachusetts_Amherst. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Eugenia M. Clerico, Alexandra K. Pozhidaeva, Rachel M. Jansen, Can
O"zden, Joseph M. Tilitsky, Lila M. Gierasch. Selective promiscuity
in the binding of E. coli Hsp70 to an unfolded protein. Proceedings
of the National Academy of Sciences, 2021; 118 (41): e2016962118
DOI: 10.1073/ pnas.2016962118 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/10/211012185717.htm

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