( enzyme the research team was surprised...)USC team reveals structure of APOBEC family protein

"Based on what is known about proteins that catalyze a similar chemical reaction, we expected it to look more like a square. But instead, it resembles a butterfly," Chen said. "It's significant because this non-canonical, butterfly shape provides new, plausible explanations of an immune deficiency disease at the molecular level."

With the Apo2 structure in hand, the team was able to deduce what likely goes wrong in patients with the rare, serious immune disorder hyper-IgM immunodeficiency syndrome type 2, or HIGM-2. The syndrome is characterized by mutations in the gene encoding AID, the activation-induced cytidine deaminase protein, and a weakened immune system.

USC biochemist Myron Goodman and his former graduate student Ronda Bransteitter collaborated with Chen's group to examine how the genetic mutations common in HIGM-2 patients might affect the structure, and therefore the function, of the AID enzyme. A professor of biological sciences and chemistry at USC College, Goodman has previously done groundbreaking work on AID and the related Apo3 APOBEC enzymes.

Using the Apo2 results as a guide, the team revealed new details about how these mutations translate into a loss of AID activity. They showed that some mutations stop AID from folding and therefore working properly, while others block its ability to interact with DNA and RNA molecules.

"The x-ray structure of Apo2 provides a clear direction for research on therapeutic strategies to deal with problems arising from either the failure of one of the APOBEC enzymes to function properly, as in HIGM-2, or from the potentially more serious problem of an enzyme working at inappropriate times and places, leading to genetic mutations that may cause cancer and other diseases," Chen said.
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Source:University of Southern California