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Unmasking the Grim Reaper
27 November 2000 7:00 pm
During the 14th century, the Black Death swept across Asia and Europe, littering streets with corpses. Centuries later, scientists are still learning how the culprit, a bacterium called Yersinia pestis, does its dirty work. One of its secrets is revealed in the 24 November issue of Science: a scissors-like protein called YopJ cuts the communication lines of human macrophage cells, leaving them unable to send SOS signals to other immune cells. That sabotage clears the way for other Y. pestis proteins to destroy the cells.
Y. pestis is infamous for causing the bubonic plague, which still infects some 2000 people a year--and for its brilliant biochemistry. Rather than climb inside macrophage cells, the bacteria hover outside and, like a molecular syringe, shoot six so-called Yersinia outer proteins (Yops) into the cells, each of which plays a distinct role in killing the cell. Last year, a team led by biochemist Jack Dixon of the University of Michigan, Ann Arbor, reported that YopJ blocks two signaling pathways that the macrophage activates to send a call for help to the immune system's B and T cells (Science, 17 September 1999, p. 1920).
But how, exactly, does YopJ accomplish this? To find out, Dixon and his colleagues ran computer programs that predicted YopJ's structure, based on its amino acid sequence. That analysis showed that YopJ closely resembles adenovirus protease (AVP), a well-known viral protein that cleaves proteins at an amino acid called cysteine. By extension, the researchers reasoned, YopJ might also be a cysteine protease, acting on similar substrates.
To test that idea, the researchers created three YopJ mutants, each altered in the key catalytic region shared with AVP. Without this region intact, the team found, the YopJ mutants couldn't block the signaling pathways in macrophage cells, nor silence their call for help. "Without this working catalytic site," Dixon concludes, "YopJ can't do its job."
"Very nice," says microbiologist Brett Finlay, of the University of British Columbia in Vancouver, about the new study. Bit by bit, Finlay says, researchers are unraveling the half-dozen virulent proteins that pack Y. pestis's punch. "This work takes us a step farther, defining the molecular machinery that allows YopJ to quiet the immune system," Finlay says.