Reporting in the Dec. 24 online edition of Nature, a USC team led by Xiaojiang Chen revealed the "unusual" crystal structure of the Apo2 enzyme.
"This three-dimensional structure offers the first mechanistic analysis of any of the APOBEC enzymes at the molecular level. These proteins are important for understanding a number of critical biological processes, such as the generation of high-affinity antibodies in response to a virus or other infection," said Chen, the study's senior author and a professor of biological sciences and chemistry in USC College.
A structural biologist, Chen has produced the first x-ray crystal structures of a number of proteins important in viruses, cancer and immunity.
In one sense, the APOBEC proteins are classic saboteurs -- they all can introduce mutations into strands of DNA or RNA. Known as deaminases, APOBEC proteins catalyze a chemical reaction that changes the "C" (cytidine) of the genetic code into a "U" or (uracil). Even a one-letter change in the code can lead to a change or loss of function in an encoded protein.
Looked at from a different perspective, however, the enzyme family plays a decidedly protective role in the cell. One notable family member, the AID protein, generates the genetic diversity required for the body to produce hundreds of billions of different antibodies, each capable of targeting a specific disease-causing agent. Others have been shown to disarm viruses like HIV and hepatitis B.
Uncontrolled, of course, the APOBEC proteins could create havoc in a cell. But normally, under the cell's tight regulation, "these are the good guys," Chen said.
When Courtney Prochnow, a graduate student in Chen's lab, first revealed the atomic structure of the enzyme, the research team was surprised by the molecule's shape.
"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.
Source:University of Southern California
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