ScienceDaily (Jan. 8, 2010) — Understanding the incredibly speedy atomic mechanisms at work when a protein transitions from one shape to another has been an elusive scientific goal for years, but an essential one for elucidating the full panoply of protein function. How do proteins transition, or interconvert, between distinct shapes without unfolding in the process? Until now, this question has been a hypothetical one, approached by computation only rather than experimentation.
The molecular path of the signaling protein from the active to the inactive state. (Credit: Francesco Pontiggia and Dorothee Kern)
In a groundbreaking study this week in Cell, Brandeis researchers reveal for the first time computationally and experimentally the molecular pathway that a protein takes to cross the energy barrier, the "climb over the mountain." The study reports how folded proteins can efficiently change shape while avoiding unfolding, a critical requirement for any protein in the cell.
Using computation and nuclear magnetic resonance (NMR) spectroscopy, the researchers were able to experimentally measure how fast the signaling nitrogen regulatory protein jumps from one shape to another, and to shed light into the atomistic pathway.
"If you think of crossing the energy barrier as reaching the summit of a mountain, what we revealed is the molecular "hiking" path the protein follows from a deep valley, to the area around the summit, and then back into another not quite-as-deep valley," said Brandeis biophysicist and Howard Hughes Medical Institute (HHMI) Investigator Dorothee Kern.
Historically, scientists had proposed that proteins must break apart, or partially unfold, between distinct active shapes. "That never made sense to me," said Kern, "because if you break the shape of the protein, you have to build it new again and that is too complicated and energy-inefficient; it would take too long."
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Cell, Volume 139, Issue 6, 1109-1118, 11 December 2009
Transient Non-native Hydrogen Bonds Promote Activation of a Signaling Protein
Alexandra K. Gardino1, 2, 3, Janice Villali1, 2, Aleksandr Kivenson1, Ming Lei1, Ce Feng Liu1, Phillip Steindel1, Elan Z. Eisenmesser1, 4, Wladimir Labeikovsky1, 5, Magnus Wolf-Watz1, 6, Michael W. Clarkson1 and Dorothee Kern1, ,
1 Department of Biochemistry and Howard Hughes Medical Institute, Brandeis University, Waltham, MA 02452, USA
Corresponding author
2 These authors contributed equally to this work
3 Present address: David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA
4 Present address: School of Medicine, University of Colorado, Denver, CO 80204, USA
5 Present address: Laboratory of Cardiac/Membrane Physiology, Rockefeller University, New York, NY 10065-7919, USA
6 Present address: Department of Chemistry, University of Umeå, Umeå SE-901 87, Sweden
Summary
Phosphorylation is a common mechanism for activating proteins within signaling pathways. Yet, the molecular transitions between the inactive and active conformational states are poorly understood. Here we quantitatively characterize the free-energy landscape of activation of a signaling protein, nitrogen regulatory protein C (NtrC), by connecting functional protein dynamics of phosphorylation-dependent activation to protein folding and show that only a rarely populated, pre-existing active conformation is energetically stabilized by phosphorylation. Using nuclear magnetic resonance (NMR) dynamics, we test an atomic scale pathway for the complex conformational transition, inferred from molecular dynamics simulations (Lei et al., 2009). The data show that the loss of native stabilizing contacts during activation is compensated by non-native transient atomic interactions during the transition. The results unravel atomistic details of native-state protein energy landscapes by expanding the knowledge about ground states to transition landscapes.
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