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.com
Volume 10, Issue 8 (Suppl)
J Proteomics Bioinform, an open access journal
ISSN: 0974-276X
Structural Biology 2017
September 18-20, 2017
9
th
International Conference on
Structural Biology
September 18-20, 2017 Zurich, Switzerland
Dynamics of knotted and entangled neurotoxic polypeptides
Marek Cieplak
Institute of Physics, Poland
W
e review the physics of processes involving large conformational transformations in knotted proteins in bulk water
and then consider folding in ribosomes and unfolding in proteasomes. Formation of a knot is demonstrated to be
facilitated by the nascent conditions at the ribosome. 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 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 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.
Biography
Marek Cieplak is the Head of Laboratory of Biological Physics, Institute of Physics, Polish Academy of Sciences in Warsaw, Poland. He completed MS, Department
of Physics, University of Warsaw, 1973; PhD, Department of Physics, University of Pittsburgh, 1977; DSc, Department of Physics, University of Warsaw, 1984.
His fields of interest are: condensed matter theory (spin waves, spin glasses, porous media, growth processes, atomic friction, river networks, nanofluidics, self-
organized nanostructures) and biological physics (large conformational changes of biomolecules within coarse-grained models, especially as induced by stretching,
proteins with knots and slipknots, protein folding, dynamics of virus capsids and other multi-proteinic structures such as a cellulosome, interaction of proteins with
solids, proteins at air-water interface, modeling of proteasomes, inference of genetic networks from the microarray data). He is the Co-author of textbook “
Theory
of Quanta
”, Oxford University Press 1992 and has published 250 research papers.
mc@ifpan.edu.plMarek Cieplak, J Proteomics Bioinform 2017, 10:8(Suppl)
DOI: 10.4172/0974-276X-C1-0100