How do cellular machines unfold misfolded proteins?

December 14, 2018, Leiden University
Unwinding a hank of yarn: how do cellular machines unfold misfolded proteins?
Credit: Leiden University

Protein chains typically fold to function. Folding is a complex process and if done correctly leads to a unique functional fold topology for a given protein chain. Other topologies are also possible but are often non-functional or toxic. These misfolded proteins are then unfolded and subsequently refolded to the correct fold topology; otherwise, they undergo degradation.

Several machines including ClpB and ClpG are responsible for unfolding a folded protein. ClpB works closely with HSP70 (DnaK) and HSP40 (DnaJ) and uses energy to unfold a chain while ClpG does not depend on HSP70. A major question is that why cells are equipped with different types of and what determines the efficiency of unfolding. Alireza Mashaghi and his team at LACDR/Leiden University solved this puzzle by monitoring unfolding of misfolded chain models at the single-molecule level. Three unfolding approaches were compared, namely, threading through a pore, pulling from the ends, and pulling by threading.

The results of this analysis, which are published on October 25th in the Journal of Physical Chemistry B, reveal that circuit topology of the folded chain critically determines the number of pathways and the efficiency of unfolding in a manner that depends on the employed mechanical approach. The study provides insights into cellular unfolding mechanisms. These findings may help in selecting optimal chaperone targets for pharmacotherapy of misfolding diseases.

Explore further: Shaping proteins to understand chaperone-related diseases

More information: Narges Nikoofard et al. Implications of Molecular Topology for Nanoscale Mechanical Unfolding, The Journal of Physical Chemistry B (2018). DOI: 10.1021/acs.jpcb.8b09454

Related Stories

Shaping proteins to understand chaperone-related diseases

April 19, 2018

Chaperones are a set of proteins that are specialised to assist proteins in the human body. They help proteins to fold to the right shape and protect them from adapting wrong shapes. The research group of Alireza Mashaghi, ...

A tale of two roads into protein unfolding

May 11, 2015

You are taking a class on origami and Mr. Otaki asks you to fold that little red piece of paper into a very elaborate design. You have to do it in a very short time. You try your best but you fail. Your origami sucks!

Chaperones just prepare proteins for folding on their own

April 26, 2018

Cellular proteins are produced as long chains of amino acids that must fold precisely into their final shape. The key players in this folding process are the so-called molecular chaperones, protein helpers that make sure ...

Remote control of transport through nanopores

May 22, 2018

In our bodies, the transfer of genetic information, viral infections and protein trafficking, as well as the synthesis and the degradation of biomolecules, are all phenomena that require the transport of molecules through ...

Recommended for you

Engineering cellular function without living cells

March 25, 2019

Genes in living cells are activated – or not – by proteins called transcription factors. The mechanisms by which these proteins activate certain genes and deactivate others play a fundamental role in many biological processes. ...

What ionized the universe?

March 25, 2019

The sparsely distributed hot gas that exists in the space between galaxies, the intergalactic medium, is ionized. The question is, how? Astronomers know that once the early universe expanded and cooled enough, hydrogen (its ...

Catalyst advance removes pollutants at low temperatures

March 25, 2019

Researchers at Washington State University, University of New Mexico, Eindhoven University of Technology, and Pacific Northwest National Laboratory have developed a catalyst that can both withstand high temperatures and convert ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.