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. |