Identifying weak interdomain interactions that stabilize the supertertiary structure of the N-terminal tandem PDZ domains of PSD-95

Inna S. Yanez Orozco, Frank A. Mindlin, Junyan Ma, Bo Wang, Brie Levesque, Matheu Spencer, Soheila Rezaei Adariani, George Hamilton, Feng Ding (), Mark E. Bowen () and Hugo Sanabria ()
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Inna S. Yanez Orozco: Clemson University
Frank A. Mindlin: Stony Brook University
Junyan Ma: Clemson University
Bo Wang: Clemson University
Brie Levesque: Stony Brook University
Matheu Spencer: Clemson University
Soheila Rezaei Adariani: Clemson University
George Hamilton: Clemson University
Feng Ding: Clemson University
Mark E. Bowen: Stony Brook University
Hugo Sanabria: Clemson University

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: Abstract Previous studies of the N-terminal PDZ tandem from PSD-95 produced divergent models and failed to identify interdomain contacts stabilizing the structure. We used ensemble and single-molecule FRET along with replica-exchange molecular dynamics to fully characterize the energy landscape. Simulations and experiments identified two conformations: an open-like conformation with a small contact interface stabilized by salt bridges, and a closed-like conformation with a larger contact interface stabilized by surface-exposed hydrophobic residues. Both interfaces were confirmed experimentally. Proximity of interdomain contacts to the binding pockets may explain the observed coupling between conformation and binding. The low-energy barrier between conformations allows submillisecond dynamics, which were time-averaged in previous NMR and FRET studies. Moreover, the small contact interfaces were likely overridden by lattice contacts as crystal structures were rarely sampled in simulations. Our hybrid approach can identify transient interdomain interactions, which are abundant in multidomain proteins yet often obscured by dynamic averaging.

Date: 2018
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DOI: 10.1038/s41467-018-06133-0

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