Unravelling a knotty problem: A simulation study of neurotoxic knotted proteins

Posted on behalf of Susannah May, guest web writer for Molecular BioSystems

Knotted proteins and their part in neurodegenerative diseases such as Huntington’s and spinal muscular atrophy have been put under scrutiny in a new HOT article recently published in Molecular Biosystems.

Two example trajectories that lead to the translocation of knotted species (yellow). Left: translocation of 1J85 when pulled in the I-N protocol. Right: unfolding of a HTT60 knotted conformation (polyQ part = red).

It’s long been known that aggregations of certain proteins have a key role in many neurodegenerative diseases, including Alzheimer’s, Parkinson’s and Huntington’s. However, exactly how these aggregations happen and how it causes disease is still a subject of intense study.

Marek Cieplak’s group at the Polish University of Sciences have used mathematical simulations to study this still-mysterious phenomenon. They looked at huntingtin, a protein involved in embryonic development. If this protein mutates, it can cause neurodegenerative diseases such as Huntington’s by forming toxic oligomers and amyloid fibres. Recent evidence has suggested that monomer forms of the protein could also be neurotoxic – Cieplak’s group theorise that this is due to knots in the structure of the protein that prevent neurodegeneration by the proteasome.

The group used mathematical simulations to create theoretical models of the knotted protein and the proteasome, and investigated the effect that the former would have on the latter under different conditions of force. Their results point to the knots being responsible for the jamming of the proteasome’s degradation mechanism. Under certain conditions proteins would stay knotted instead of untying, hindering normal neurodegeneration and leading to neurotoxic build-up of proteins.

The results will help to provide greater understanding of the mechanisms behind genetic diseases such as Huntington’s, paving the way for future experimental studies and, hopefully one day, the development of new and effective treatments.


Read the full article here:

Unfolding knots by proteasome-like systems: simulations of the behaviour of folded and neurotoxic proteins
Michał Wojciechowski, Àngel Gómez-Sicilia, Mariano Carrión-Vázquez and Marek Cieplak
DOI: 10.1039/C6MB00214E




Susannah May is a guest web writer for the RSC Journal blogs. She currently works in the Publishing Department of the Royal Society of Chemistry, and has a keen interest in biology and biomedicine, and the frontiers of their intersection with chemistry. She can be found on Twitter using @SusannahCIMay.

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