New discoveries on protein misfolding

A study has now identified 21 proteins that specifically bind to a protein called ataxin-1 and influence its folding or misfolding. A special structure called "coiled-coil-domain" was also discovered.

Researchers from the Max Delbruck Center for Molecular Medicine (MDC) Berlin-Buch, Germany, along with their peers at the Université Paris Diderot, Paris, France, conducted the study.

Neurodegenerative diseases such as Huntington’s disease or spinocerebellar ataxias (SCAs), which are characterised by a advancing loss of neurons in the brain, can be caused by misfolded proteins.

Misfolded proteins can amass into insoluble masses that join with other proteins and  are poisonous to cells.

The protein that has now been studied, Ataxin-1, is extremely prone to misfolding because of hereditary gene defects that cause neurodegenerative diseases.

This is due to an overload of the amino acid glutamine in the chains that make up atain-1. It's estimated that for a cell to be toxic, 40 repeats of glutamine misfolding are required.

Of the 21 identified proteins that mostly interact with ataxin-1 and manipulate its folding or misfolding, 12 augment the misfolding of the protein through increasing its toxicity for the nerve cells.

This means that they encourage the development of harmful protein aggregate structures. On the other hand, nine proteins prevent the misfolding, through reducing its toxicity.

Coiled coil domains were discovered by the researchers as a common feature in the structure of those proteins. These special structures increase aggregation and toxicity in the proteins and are named after the fact that they look like a helix or double twisted spiral.

The structures encourage aggregation by the proteins that interact with ataxin-1 enhancing the toxic effect of mutated ataxin-1.

"A careful analysis of the molecular details could help to discover drugs that suppress toxic processes," said the researchers.

Posted by Fiona Griffiths