PROTEINS IN TRANSITION CHEMICAL BIOLOGY: Conformational change proceeds along surprising path
P
Hydrogen bonding assists the conformational change between a protein’s inactive (blue) and active (red) states.
ROTEINS CHANGE shape frequently to fulfill
their duties. For instance, proteins that organisms use for signaling possess one shape when they’re inactive and another shape once they’ve been activated to transmit a signal. Now, a group of biochemists at Brandeis University have for the first time observed how a signaling protein shifts between these two different conformations. Conventional wisdom holds that most signaling proteins’ conversion from an inactive to an active conformation is triggered by phosphorylation. However, Dorothee Kern and her Brandeis colleagues discovered that a bacterial signaling protein called nitrogen regulatory protein C (NtrC) switches between these two conformations regardless of whether the protein is phosphorylated. With the help of nuclear magnetic resonance dynamics experiments and computational techniques, they found that phosphorylation of the protein occurs only after the conformational change. Phosphorylation stabilizes the active state, which as a result becomes the energetically favored conformation (Cell 2009, 139, 1109). After the protein carries out its signaling task, it is quickly dephosphorylated. The protein then spends
most of its time in the inactive conformation, which is energetically favored when the protein lacks the phosphate group. The Brandeis team also tackled another long-held belief, which posits that a protein has to partially unfold to convert from one conformation to another. Kern never bought into that theory. She reasoned that unfolding would be risky because a partially unfolded protein would be vulnerable to degradation or aggregation, which can lead to disease. Now, Kern’s team has demonstrated that NtrC changes conformation without unfolding. The group discovered that nonnative hydrogen bonds form fleetingly within the protein, helping it change shape in a rapid, step-by-step manner in which bonds are broken and formed one at a time rather than all at once. This controlled reconfiguration avoids the risks of unfolding and also lowers the energy barrier that separates the inactive and active conformations. Kern says NtrC makes a good subject because the molecule is small enough to study with NMR and because it undergoes a large and complex conformational change. She believes the NtrC findings will extend to other proteins. She also expects the insight the research provides into the dynamic way in which proteins work will improve the design of artificial enzymes to carry out desired functions. The Brandeis team’s “studies are remarkable,” David D. Boehr, a Pennsylvania State University chemist who studies protein dynamics, notes in a Cell commentary about the work. “They not only reveal new insights into the activation mechanism of NtrC, but they also provide a methodology to elucidate the connections between the energy landscapes of folding and function in other proteins.”—SOPHIE ROVNER
F RAN CESCO P O N T IGGIA AN D DO ROT HEE K ER N
NEWS OF THE WEEK
CLIMATE CHANGE Satellite data show water vapor increases CO2 warming ane, and water vapor, acquired by the Atmospheric Infrared Sounder (AIRS) aboard NASA’s weather satellite Aqua. The AIRS instrument measured gas levels in the mid-troposphere, which lies 5–12 km above Earth’s surface. Scientists have believed for years that water vapor plays a key role in climate change, but this is the first time observations have corroborated this. The new data validate models that have predicted that when global temperatures rise from increased atmospheric CO2, the atmosphere becomes more humid, which further increases temperatures. Clouds with increased moisture, and thus increased reflectivity, could potentially reduce the effect, Dessler said.
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DECEMBER 21, 2009
NASA’s AIRS instrument mapped global tropospheric CO2 levels. Red indicates higher levels. The AIRS project was to complement NASA’s Orbiting Carbon Observatory, which crashed minutes after launch (C&EN, March 2, page 30). OCO would have orbited three minutes ahead of Aqua and mapped CO2 sources and sinks from Earth’s surface to 20 km high. The scientists said they hope NASA will eventually launch a new OCO. “We are keeping a spot warm for it in front of Aqua,” AIRS team leader Moustafa Chahine said.—ELIZABETH WILSON
NASA
A new set of satellite data indicates that further global warming is “essentially guaranteed” due to the amplifying effects of water vapor on warming from the greenhouse gas CO2, scientists announced last week. Water vapor—which is itself a greenhouse gas—will more than double the climate warming effects from CO2, unless some as-yet-unknown factor cancels MORE ONLINE out that effect, climatologist Andrew Dessler of Texas A&M University said at the American Geophysical Union meeting in San Francisco. Dessler and his colleagues unveiled seven years’ worth of global maps of greenhouse gases, including CO2, meth-
