Dorothee Kern is changing the way scientists think about enzymes—proteins that speed up chemical reactions.

Despite their heated scientific debates as kids in Germany, Dorothee Kern never imagined turning to her little brother to collaborate on her research. But Christian Huebner, three years her junior, is now a physicist and offered just the know-how Kern needed to resolve a puzzle about the behavior of a restless protein.

With his help, Kern, who has previously collaborated with her parents—also scientists in Germany—made sense of her experimental observations that the protein could adopt three distinct conformations in one crystal. In the process, she turned a long-standing biochemistry assumption on its head.

Kern, an HHMI investigator at Brandeis University, studies the dynamics of enzymes—proteins that speed up chemical reactions by clamping onto one or more substrates and efficiently converting them into products. In this case, she was studying adenylate kinase, an enzyme that processes ATP, ADP, and AMP—molecules that give cells energy and are building blocks of DNA. Adenylate kinase exists in every organism, from bacteria to humans. Kern wanted to know how the enzyme adapted to one of its most extreme environments—inside bacteria that thrive at 220 degrees Fahrenheit in deep ocean vents. Most proteins unravel at such high temperatures.

She already knew the molecular structure of adenylate kinase at more moderate temperatures but not what the heat-loving version looked like. “We really needed a high-resolution structure to see subtle differences,” says Kern.

She and her colleagues turned to x-ray crystallography—they bombarded crystallized protein with x-rays and used the resulting diffraction pattern to determine the protein's three-dimensional arrangement. “We thought it would be easy,” says Kern.

		Interview With Dorothee Kern Hear Dorothee Kern talk about what it was like to collaborate with her brother, and what her results mean in the broader context of biology. Running Time: 6:22 Play Audio Protein in Motion The twitching motion of the enzyme adenylate cyclase in the absence of any substrate. View Animation

Not quite. The data gave a jumbled picture of atoms that seemingly existed in three places at once. Kern's take on this puzzling result: three different structures were present in a single crystal.

“We had one crystal of one unique protein, but three conformations of the protein,” says Kern. “These are just snapshots though—static and frozen in the crystal.”

What Kern needed was a way to measure whether the protein, when it wasn't stuck in a crystal, actively alternated between these structures. Nuclear magnetic resonance (NMR), which can detect the movement of atoms, provided just such an approach. Using NMR, Kern's team calculated that the protein switched conformation about every millisecond or so, but they were not able to see exactly which conformations.

Photo: Leah Fasten

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