Disordered proteins follow diverse transition paths as they fold and bind to a partner

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Science  12 Jun 2020:
Vol. 368, Issue 6496, pp. 1253-1257
DOI: 10.1126/science.aba3854

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Shedding light on disordered proteins

Disordered proteins often fold as they bind to a partner protein. There could be many different molecular trajectories between the unbound proteins and the bound complex. Most methods to measure transition paths rely on monitoring a single distance, making it difficult to resolve complex pathways. Kim and Chung used fast three-color single-molecule Foster resonance energy transfer (FRET) to simultaneously probe distance changes between the two ends of an unfolded protein and between each end and a probe on the partner protein. They show that binding can be initiated by diverse conformations and that the molecules are held together by non-native interactions as the disordered protein folds. This allows the association to be diffusion limited because most collisions lead to binding.

Science, this issue p. 1253


Transition paths of macromolecular conformational changes such as protein folding are predicted to be heterogeneous. However, experimental characterization of the diversity of transition paths is extremely challenging because it requires measuring more than one distance during individual transitions. In this work, we used fast three-color single-molecule Förster resonance energy transfer spectroscopy to obtain the distribution of binding transition paths of a disordered protein. About half of the transitions follow a path involving strong non-native electrostatic interactions, resulting in a transition time of 300 to 800 microseconds. The remaining half follow more diverse paths characterized by weaker electrostatic interactions and more than 10 times shorter transition path times. The chain flexibility and non-native interactions make diverse binding pathways possible, allowing disordered proteins to bind faster than folded proteins.

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