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Unfolding knots by proteasome-like systems: simulations of the behaviour of folded and neurotoxic proteins

Content Provider	Royal Society of Chemistry (RSC)
Author	Carrión-Vázquez, Mariano Cieplak, Marek Gómez-Sicilia, Àngel Wojciechowski, Michał
Copyright Year	2016
Abstract	Knots in proteins have been proposed to resist proteasomal degradation. Ample evidence associates proteasomal degradation with neurodegeneration. One interesting possibility is that indeed knotted conformers stall this machinery leading to toxicity. However, although the proteasome is known to unfold mechanically its substrates, at present there are no experimental methods to emulate this particular traction geometry. Here, we consider several dynamical models of the proteasome in which the complex is represented by an effective potential with an added pulling force. This force is meant to induce the translocation of a protein or a polypeptide into the catalytic chamber. The force is either constant or applied periodically. The translocated proteins are modelled in a coarse-grained fashion. We do comparative analysis of several knotted globular proteins and the transiently knotted polyglutamine tracts of length 60 alone and fused in exon 1 of the huntingtin protein. Huntingtin is associated with Huntington's disease, a well-known genetically determined neurodegenerative disease. We show that the presence of a knot hinders and sometimes even jams translocation. We demonstrate that the probability to do so depends on the protein, the model of the proteasome, the magnitude of the pulling force, and the choice of the pulled terminus. In any case, the net effect would be a hindrance in the proteasomal degradation process in the cell. This would then yield toxicity via two different mechanisms: one through toxic monomers compromising degradation and another by the formation of toxic oligomers. Our work paves the way for the mechanistic investigation of the mechanical unfolding of knotted structures by the proteasome and its relation to toxicity and disease.
Starting Page	2700
Ending Page	2712
Page Count	13
File Format	HTM / HTML PDF
ISSN	1742206X
Volume Number	12
Issue Number	9
Journal	Molecular BioSystems
DOI	10.1039/c6mb00214e
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Open
Subject Keyword	Exon Huntingtin Neurodegeneration Henry E. Huntington Huntington Nerve tract Knot theory Peptide Protein Proteasome Molecular geometry
Content Type	Text
Resource Type	Article
Subject	Molecular Biology Biotechnology

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