Transient misfolding dominates multidomain protein folding

Alessandro Borgia (), Katherine R. Kemplen, Madeleine B. Borgia, Andrea Soranno, Sarah Shammas, Bengt Wunderlich, Daniel Nettels, Robert B. Best, Jane Clarke () and Benjamin Schuler ()
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Alessandro Borgia: University of Zurich
Katherine R. Kemplen: University of Cambridge
Madeleine B. Borgia: University of Zurich
Andrea Soranno: University of Zurich
Sarah Shammas: University of Cambridge
Bengt Wunderlich: University of Zurich
Daniel Nettels: University of Zurich
Robert B. Best: Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
Jane Clarke: University of Cambridge
Benjamin Schuler: University of Zurich

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: Abstract Neighbouring domains of multidomain proteins with homologous tandem repeats have divergent sequences, probably as a result of evolutionary pressure to avoid misfolding and aggregation, particularly at the high cellular protein concentrations. Here we combine microfluidic-mixing single-molecule kinetics, ensemble experiments and molecular simulations to investigate how misfolding between the immunoglobulin-like domains of titin is prevented. Surprisingly, we find that during refolding of tandem repeats, independent of sequence identity, more than half of all molecules transiently form a wide range of misfolded conformations. Simulations suggest that a large fraction of these misfolds resemble an intramolecular amyloid-like state reported in computational studies. However, for naturally occurring neighbours with low sequence identity, these transient misfolds disappear much more rapidly than for identical neighbours. We thus propose that evolutionary sequence divergence between domains is required to suppress the population of long-lived, potentially harmful misfolded states, whereas large populations of transient misfolded states appear to be tolerated.

Date: 2015
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DOI: 10.1038/ncomms9861

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