December 17, 1999
Viral Harpoon Reveals Ancestry of Measles, Mumps Viruses
A computer-enhanced image of the viral harpoon that
measles and mumps viruses use to spear host cells.
The red color indicates the fusion protein's negatively
charged amino acids; blue represents positively charged
amino acids.
When viruses infect cells, they employ molecular "harpoons" to snare
their intended target. Recently, a team of scientists identified and
determined the three-dimensional structure of the harpoon protein used
by a large family of pathogenic viruses to grab hold of and fuse to
host cells. Surprisingly, the protein's structure suggests that viruses
that cause measles and mumps may be viral cousins of HIV, influenza and
Ebola virus.
The research team, which included Robert
Lamb of the Howard Hughes Medical Institute at Northwestern
University, believes that its discovery may help lead to the
development of drugs that can prevent viral infections by jamming this
critical infectious machinery. The researchers reported their findings
in the March 26, 1999, issue of the journal Molecular Cell.
Lamb and Northwestern University colleagues Theodore Jardetzky, Kent
Baker and Rebecca Dutch were studying a member of the paramyxovirus
family, which includes the viruses that cause measles, mumps and
respiratory syncytial viral infection (RSV) – a leading cause of
hospitalization in young children. Other paramyxoviruses cause croup,
pneumonia and bronchitis in young children, and members of this family
can infect a variety of mammals and birds.
The scientists crystallized the fusion protein of a paramyxovirus
that infects monkeys and used x-ray crystallography to determine the
protein’s three-dimensional structure. This analytical process
involves shining an intense x-ray beam through a protein crystal, and
then deducing the protein’s structure by analyzing the patterns of
light that emerge from the crystal.
Although the scientists studied the fusion protein of only one
paramyxovirus, they are confident that the structural finding applies
to the entire paramyxovirus family. Previous analyses of the basic
"primary" structure – the order, or sequence, of amino acids that
make up a protein – of many different paramyxovirus fusion protein
molecules revealed that their basic structures are all similar.
But when the scientists analyzed the three-dimensional structure of
the simian virus fusion protein, they were surprised to discover close
structural similarities to fusion proteins from HIV, influenza and
Ebola, said Lamb. Aside from this similarity, he said, "all these
viruses have very different strategies for infecting cells and
insinuating viral genetic material into the target cells to commandeer
their machinery."
According to Lamb, the similarity among such widely varied viruses
suggests that they might have had some common ancestor that shared a
primitive version of the fusion protein. It is impossible at this
point, however, to pinpoint the evolutionary origin of that ancestry,
he said.
Regardless, said Lamb, "knowing the structure of this one fusion
protein may lead to the development of drugs capable of thwarting the
action of the fusion proteins of other members of the paramyxovirus
family, and even possibly its distant viral cousins." At the least, he
added, these findings will spur further studies involving other
medically important viruses.
Specifically, determining the three-dimensional structure of the
fusion protein sheds new light on the key event in paramyxovirus
infection — when the virus unfolds itself to reveal a spikelike
protein that is launched into the gel-like outer membrane of the target
cell. "It's much like a harpoon going into a target," said Lamb.
He emphasized, however, that more research is needed to answer two
important questions: What triggers the harpoon molecule to unfurl, and
how does the fusion protein refold itself to draw the virus toward the
ensnared target cell? "What happens there is a mystery," he said. "It's
like spearing a shark. It’s relatively easy to spear it, but
getting it onboard the boat is more difficult, and we don’t quite
know how this kind of process happens in these viruses."
Image: Robert Lamb/HHMI at Northwestern University
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