A new study by the University of Michigan (UM) and the Rockefeller University reveals not only how one of the proteins in human bodies latches onto foreign invaders, but also how some viruses, including the human immunodeficiency virus (HIV), evade capture.
Humans have evolved dynamic defense mechanisms against the viruses that seek to infect our bodies-proteins that specialize in identifying, capturing and destroying the genetic material that viruses try to sneak into our cells, researchers said.
A previous study from the Rockefeller University revealed that the protein in question, called zinc-finger antiviral protein (ZAP) grabs onto only one specific sequence of neighboring nucleotides, the building blocks of DNA and RNA: a cytosine followed by a guanine, or a CG dinucleotide.
Human RNAs have few CG dinucleotides, and HIV RNA has evolved to mimic this characteristic.
A team of researchers from the University of Michigan Life Sciences Institute and the Rockefeller University wanted to determine how ZAP recognizes the virus's genome, and how some viruses avoid it.
Using a piece of viral RNA that was genetically altered to include extra CG sequences, the researchers determined the structure of the ZAP protein bound to RNA, exposing the mechanisms that enable the protein to be so selective.
The researchers discovered that ZAP binds to the viral RNA at only one of the four "zinc fingers" on the protein that they considered potential binding sites.
They further demonstrated that even a tiny change to that one binding site, altering just a single atom, hampered ZAP's binding ability.
Working in cells, researchers from the Rockefeller University found similar results when they altered ZAP's composition.
They created mutant versions of ZAP that were expressed in cells infected with either normal HIV or a version of the virus enriched with CG sequences.
The mutant ZAP proteins were less able to recognize CG-enriched regions of the viral RNA in cells. They also exhibited increased binding to areas of the RNA that were not rich in CG dinucleotides, indicating that alterations impair ZAP's ability to distinguish viral RNA from human RNA.
"Natural selection appears to have shaped the ZAP protein structure in such a way to optimize the discrimination of non-self from self RNA, based on CG dinucleotide content," said Paul Bieniasz, head of the Laboratory of Retrovirology at the Rockefeller. "However, successful viruses are often one step ahead in a molecular arms race."
"This is the crucial first step in a complicated story of how the cell eventually degrades the virus's RNA," said Janet Smith, an LSI research professor and professor of biological chemistry at UM Medical School. "And now we know how the step is executed, and why it is not effective on HIV and other viruses that lack this CG sequence."
The study was published on Monday in Proceedings of the National Academy of Sciences.
