Denatured Proteins Rescued By Trio Of Chaperones

July 10, 1998

You can't unfry an egg-or maybe you can. Researchers from the Howard Hughes Medical Institute at the University of Chicago report in the July 10 issue of Cell that a powerful combination of heat shock proteins (Hsps) can return aggregated proteins, until now thought to be permanently entangled, to their functional, native states.

Previously, scientists thought that Hsps could only prevent proteins from aggregating as temperatures rise. But now, Susan Lindquist, Ph.D., and colleague John Glover, Ph.D., have shown that protein snarls can actually be rescued by Hsp104 with the assistance of two other heat shock proteins.

Heat is a protein's enemy. As an egg fries, its proteins, which are made of chains of molecules called amino acids precisely folded into spirals, loops and sheets, begin to loose their shape. Sticky bits from the interior of the protein get exposed, and adhere to each other, forming disordered globs, or aggregates (this is why egg whites change from a clear liquid-like state to a white solid). In the body, heat stress can do the same thing to proteins, making them dysfunctional.

When exposed to sudden shifts in temperature, all organisms make heat shock proteins, otherwise known as chaperones, which protect (to some extent) against denaturation. The chaperone's job is to protect unfolded proteins from getting into more trouble (aggregating) until they have had a chance to refold to their normal, functional form.

"The general strategy for cells is to prevent aggregation from happening in the first place," says Lindquist, Howard Hughes Investigator and professor in the Department of Molcular Genetics and Cell Biology.

"We thought that Hsps bind to sticky surfaces presented by denatured proteins to prevent them from interacting and forming a blob, and they do. But now we have shown that at least one heat shock protein, namely Hsp104, has the ability to rescue proteins that have already aggregated. This ability is essential to the survival of cells facing extreme heat."

To find out where and how Hsp104 works, the researchers tested its ability to prevent aggregation and promote refolding of heat denatured firefly luciferase. They found that Hsp104 alone could not untangle the clusters. However, when other heat shock proteins from yeast were added, reactivation of luciferase was observed.

Lindquist and Glover pinpointed two heat shock proteins that were observed to interact with Hsp104-Hsp40 and Hsp70. When these chaperones were added to the aggregated luciferase together with Hsp104, there was a profound increase in the amount of recovered functional protein.

"When we put the two elements together, the Hsp40 and 70 plus Hsp104, there was a synergistic effect and we saw incredible amounts of refolding," says Glover.

Lindquist and Glover think that Hsp40 and Hsp70 help to partially stabilize proteins as they begin to aggregate. Then, Hsp104 helps the glob come apart so that Hsp40 and Hsp70 can refold individual proteins to their native states.

"Understanding how Hsp104 works could help us to better understand protein folding disorders, such as Alzheimer's and mad cow disease," says Lindquist. "It could also shed light on how disease organisms that are carried by cold blooded insects survive the sudden temperature transition as they are injected into their warm-blooded hosts," says Glover.

Chaperones from bacteria, plants, lower animals and humans are virtually identical. This means that they probably evolved to protect the very earliest organisms to inhabit our planet and have remained essentially unchanged through billions of years.

University of Chicago Medical Center

Related Proteins Articles from Brightsurf:

New understanding of how proteins operate
A ground-breaking discovery by Centenary Institute scientists has provided new understanding as to the nature of proteins and how they exist and operate in the human body.

Finding a handle to bag the right proteins
A method that lights up tags attached to selected proteins can help to purify the proteins from a mixed protein pool.

Designing vaccines from artificial proteins
EPFL scientists have developed a new computational approach to create artificial proteins, which showed promising results in vivo as functional vaccines.

New method to monitor Alzheimer's proteins
IBS-CINAP research team has reported a new method to identify the aggregation state of amyloid beta (Aβ) proteins in solution.

Composing new proteins with artificial intelligence
Scientists have long studied how to improve proteins or design new ones.

Hero proteins are here to save other proteins
Researchers at the University of Tokyo have discovered a new group of proteins, remarkable for their unusual shape and abilities to protect against protein clumps associated with neurodegenerative diseases in lab experiments.

Designer proteins
David Baker, Professor of Biochemistry at the University of Washington to speak at the AAAS 2020 session, 'Synthetic Biology: Digital Design of Living Systems.' Prof.

Gone fishin' -- for proteins
Casting lines into human cells to snag proteins, a team of Montreal researchers has solved a 20-year-old mystery of cell biology.

Coupled proteins
Researchers from Heidelberg University and Sendai University in Japan used new biotechnological methods to study how human cells react to and further process external signals.

Understanding the power of honey through its proteins
Honey is a culinary staple that can be found in kitchens around the world.

Read More: Proteins News and Proteins Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to