Researchers led by Leemor Joshua-Tor at Cold Spring Harbor Laboratory (CSHL) have shed new light on how a protein called Dis312 makes use of numerous recognition sites in order to identify messages that are flagged for decay.
Dis3l2 is a molecular machine that helps to preserve the character of stem cells. It serves as the executioner of an elegant pathway that prevents stem cells from changing into other cell types. The protein does this by acting like a garbage disposal for messages in the cell, cutting them up until they no longer encode useful information. But Dis3l2 is necessarily highly specific. While it must degrade messages that would alter the fate of the stem cell, discarding the wrong message could have devastating consequences.
Therefore, Dis3l2 only targets specific messages that have been marked with a molecular flag, known as a "poly-U" chain. The enzyme ignores the majority of messages in the cell - those that go on to encode proteins and other critical messages - whose ends are decorated with a different type of chain, called "poly-A" tail.
But how does the enzyme "read" the poly-U chain? Christopher Faehnle, PhD and Jack Walleshauser, lead authors on the paper, found that the interior of the funnel contains more than a dozen contacts that interact specifically with the poly-U chain. "Together, all of these points create a sticky web that holds the poly-U sequence deep within the enzyme," says Faehnle. "But other chains don't interact - they can slide right out. It has helped us understand how an enzyme can differentiate between two sequences in the cell."
More than that, the work provides insight into how a stem cell maintains its identity. "Misregulation of any step in this pathway leads to developmental disorders and cancer," says Joshua-Tor. "We now have a much better appreciation of the terminal step, a critical point of control."