In the constantly morphing field of protein structure, scientists at The Scripps Research Institute offer yet another surprise: a common "chaperone" protein in cells thought to help other proteins fold has been shown instead to loosen them.
The study was published in the April 3 issue of Nature Structural & Molecular Biology.
The research offers the first structural insights into the shape of a "client" protein in the presence of a helper or "chaperone" protein. Specifically, the study examined the client protein p53 tumor suppressor and its interactions with chaperone heat shock protein 90 (Hsp90).
"It was a real surprise to find that, when bound to Hsp90, p53 is loosened and becomes less ordered, forming a molten globule-like state," said the study's lead investigator, molecular biologist Professor H. Jane Dyson. "This contradicts what everyone thought of as the function of chaperone proteins—to help other proteins fold into a well-defined three-dimensional structure."
The findings add to scientists' new understanding of proteins, now thought not only to constantly change shape to perform different functions, but also to be active when unfolded.
It was once thought that proteins could be active only if they were neatly folded into a compact shape and that this structure defined its function. Then Scripps Research investigators Dyson and Professor Peter Wright, as well as others, discovered that unfolded "disordered" proteins (also known as "intrinsically unstructured proteins") could also be active.
One way these intrinsically disordered proteins act is by folding when they bind to other molecules and performing a function such as potentiating cellular signaling or turning on the transcription of a gene.
The disordered protein might then dissociate from this partner, unfold, and perhaps bind to a different molecule in a new shape. Thus, these proteins can constantly move between unstructured and ordered states, interacting with many different partners as part of the "proteostasis." of the cell.
"We are realizing that proteins are a lot more versatile than we understood in the past," said Dyson.
Breaking New Ground
In the new Nature Structural & Molecular Biology study, the team set out to better understand the structural biology of the Hsp90/p53 complex.
Both Hsp90 and p53 are crucial to cell functioning. About one percent of proteins in a typical cell are Hsp90 chaperone molecules, and they are known to perform a number of functions, including acting as "holding" proteins for hormone receptors. The tumor suppressor p53 is a crucial cell cycle regulator; in fact, most mutations seen in cancers occur in the DNA-binding domain of p53, which is also the site of its interaction with Hsp90.
"A lot of researchers have studied the interactions of Hsp90 and its client proteins," said Dyson. "None of these studies was able to pinpoint either what the client protein looked like in the complex or what part of Hsp90 was contacting the client."
In the new study, the team used protein nuclear magnetic resonance (NMR) spectroscopy; Scripps Research has some of the world's most powerful NMR spectrometers. Still, the research took several years to complete, given the complicated nature of the proteins, their large size, and their weak interactions.
The data ultimately showed Hsp90 acted to loosen up, or unfold, p53.
The authors suggest the interactions of Hsp90 with its client proteins are tuned to tasks as needed within a cell. "Our study demonstrates that the interaction is surprisingly non-specific," said Dyson, "and that rather than making a distinct complex, the Hsp90 causes a change in the overall structure of the client."
Hsp90 could perform other, as-of-yet-unknown functions, she added. "This is just the beginning of understanding how these important, and very common, chaperone proteins are functioning."
The first author of the study was Sung Jean Park of Scripps Research and the Gachon University School of Medicine and Science. In addition to Dyson, other authors of the study are Brendan N. Borin and Maria A. Martinez-Yamout of Scripps Research.
The research was funded by grants from the National Institutes of Health and the Korea Research Foundation.
About The Scripps Research Institute
The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neuroscience, and vaccine development, as well as for its insights into autoimmune, cardiovascular, and infectious disease. Headquartered in La Jolla, California, the institute also includes a campus in Jupiter, Florida, where scientists focus on drug discovery and technology development in addition to basic biomedical science. Scripps Research currently employs about 3,000 scientists, staff, postdoctoral fellows, and graduate students on its two campuses. The institute's graduate program, which awards Ph.D. degrees in biology and chemistry, is ranked among the top ten such programs in the nation.
Mika Ono | EurekAlert!
Researchers uncover protein-based “cancer signature”
05.12.2016 | Universität Basel
The Nagoya Protocol Creates Disadvantages for Many Countries when Applied to Microorganisms
05.12.2016 | Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH
Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water
In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
05.12.2016 | Earth Sciences
05.12.2016 | Physics and Astronomy
05.12.2016 | Life Sciences