Blockade in cellular waste disposal: Scientists show how protein aggregates disrupt the molecular balance of the cell

Jun 21, 2013
Blockade in cellular waste disposal: Scientists show how protein aggregates disrupt the molecular balance of the cell
PolyQ aggregates (red) inhibit degradation of misfolded protein (green) and accumulate cytosolic inclusions. The nucleus is stained in blue. Credit: Sae-Hun Park, Copyright: MPI of Biochemistry.

Proteins can only perform their complex functions in the cell when they assume a specific three-dimensional structure for each respective task. Because misfolded proteins are often toxic, they are immediately refolded or degraded. Scientists of the Max Planck Institute (MPI) of Biochemistry in Martinsried near Munich have now shown in the yeast model that specific protein aggregates block an important degradation pathway for defective proteins – and thus disrupt the fragile molecular balance of the cell. The results of the study have now been published in the journal Cell.

in cells can cause severe diseases such as Huntington's disease. The massive movement disorders that appear with this disease are likely caused by aggregates of specific proteins, the polyQ proteins. Scientists of the research department Cellular Biochemistry headed by F.-Ulrich Hartl have now shown how these protein aggregates, commonly known as plaques, seriously disrupt cellular homeostasis.

Cells in the balance

The entire set of all is referred to as the proteome, whose composition is determined by a delicate balance of and degradation. This process is regulated at several levels. Key helpers here are the which aid the proteins in proper folding or lead them to degradation if the misfolding is irreparable. Among other things, this procedure serves to prevent the formation of protein plaques. Hartl's team has now succeeded in demonstrating that polyQ aggregates in yeast primarily have an effect on the chaperone Sis1p.

This molecule functions as a cellular shuttle: It transports misfolded proteins from the cytosol into the , where they are degraded. The harmful polyQ plaques block this process by intercepting Sis1p. "As a result, misfolded proteins accumulate in the cell, which may contribute to the toxicity of polyQ aggregates," said Sae-Hun Park, scientist at the MPI of Biochemistry and first author of the study.

Similar processes may occur in polyQ diseases in humans. Also in mammalian cells, misfolded proteins are transported from the into the nucleus. Here the chaperone DnajB1 plays a role similar to Sis1p in the yeast model. Contrary to prevailing opinion, Hartl's team even assumes that this degradation pathway is the most important means of clearance of misfolded proteins from the cell interior. Further studies shall now show whether and to what extent these fundamental processes play a role in the pathogenic protein plaques.

Explore further: Life's extremists may be an untapped source of antibacterial drugs

More information: Park, S. PolyQ Proteins Interfere with Nuclear Degradation of Cytosolic Proteins by Sequestering the Sis1p Chaperone, Cell, June 20, 2013. DOI: 10.1016/j.cell.2013.06.003

Related Stories

Transmission routes of spreading protein particles

Mar 27, 2013

In diseases like Alzheimer's and Parkinson's endogenous proteins accumulate in the brain, eventually leading to the death of nerve cells. These deposits, which consist of abnormally formed proteins, are supposed to migrate ...

Scientists gain new insights into protein disposal

May 28, 2013

Cells have a sophisticated system to control and dispose of defective, superfluous proteins and thus to prevent damage to the body. Dr. Katrin Bagola and Professor Thomas Sommer of the Max Delbrück Center for Molecular Medicine ...

Recommended for you

Cohesin molecule safeguards cell division

Nov 21, 2014

The cohesin molecule ensures the proper distribution of DNA during cell division. Scientists at the Research Institute of Molecular Pathology (IMP) in Vienna can now prove the concept of its carabiner-like ...

Nail stem cells prove more versatile than press ons

Nov 21, 2014

There are plenty of body parts that don't grow back when you lose them. Nails are an exception, and a new study published in the Proceedings of the National Academy of Sciences (PNAS) reveals some of the r ...

Scientists develop 3-D model of regulator protein bax

Nov 21, 2014

Scientists at Freie Universität Berlin, the University of Tubingen, and the Swiss Federal Institute of Technology in Zurich (ETH) provide a new 3D model of the protein Bax, a key regulator of cell death. When active, Bax ...

Researchers unwind the mysteries of the cellular clock

Nov 20, 2014

Human existence is basically circadian. Most of us wake in the morning, sleep in the evening, and eat in between. Body temperature, metabolism, and hormone levels all fluctuate throughout the day, and it ...

User comments : 0

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.