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Detailed 3-D image catches a key regulator of neural stem cell differentiation in action

the enzyme RNA polymerase II from reading and switching on neuronal genes in tissues where they shouldn't be expressed, such as skin, muscle and liver. In the nervous system Scp1 is switched off, enabling RNA polymerase II to efficiently transcribe information encoded by neuronal genes and driving the maturation of neural stem cells into specialized neurons.

"Scp1 is an interesting twist on how genes can be regulated during development," says Pfaff. "In the past there has been a lot of emphasis on chromatin modifications and physical access to genes, but Scp1 regulates the activity of the enzyme that transcribes genes directly," he adds.

Scp1 is not the only protein that directly influences the activity of RNA polymerase II. A constantly fluctuating brigade of enzymatic foot soldiers regulates RNA polymerase II's activity by chemically modifying the long cord-like tail that hangs from its globular structure, like a chain on a light fixture.

Enzymes called kinases turn the "light" on by adding small phosphate chemical groups - giving RNA polymerase the go-ahead to transcribe genes - while removal of those phosphates by phosphatases like Scp1 turns out the light, effectively stopping RNA polymerase in its tracks.

Noel and postdoctoral fellow Yan Zhang, Ph.D, analyzed the crystal structure of Scp1 and RNA polymerase together and obtained a 3-dimensional image showing how Scp1 hangs onto the seven amino acid residues reiterated in the polymerase tail. "We captured Scp1 bound to a single seven amino-acid long repeat containing specific phosphates," explains Zhang, the paper's first author. "It turns out that only three amino acids are important for Scp1's ability to know how to remove phosphates from RNA polymerase."

She adds that knowing how enzymes like Scp1 precisely recognize that seven amino acid stretch is exactly the kind of "unambiguous information relevant for the design of a chemical inhibitor by a process
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Contact: Gina Kirchweger
Kirchweger@salk.edu
858-453-4100
Salk Institute
7-Dec-2006


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