 It
sounds like a cousin of the Borg from Star Trek, drifting through
space in search of prey. And in its own
micro universe a phage is just as deadly as its fictional relative.
It is a virus that infects bacteria by churning out up to
10 trillion variants of a particular protein.
Now a team led by UCSD biochemists has figured out the mechanism
that permits a phage to be such an amazing protein-producing machine.
Their results were published in the October issue of the journal
Nature Structural and Molecular Biology.
“This is only the second type of massively variable protein ever
discovered,” explains Partho Ghosh, a professor of chemistry
and biochemistry at UCSD who headed the research team. “Only
antibodies have more variation than this protein in phage. However,
the genetic mechanism used by the phage to generate this diversity
is completely different from that used by animals to produce
antibodies, and has the advantage of giving the protein greater
stability.”
The function of the massively variable phage protein is to
tether the phage to the bacteria they infect. The phage “predator” protein
fits into a “prey” protein on the bacteria like a
three-dimensional puzzle piece. However, bacteria are constantly
changing the proteins
on their surface.
An evolutionary arms race ensues in which the phage must generate
many different predator proteins for at least one to have an
acceptable fit with the prey protein.
By altering just 12 sites on the predator protein, the phage
can vary the protein 10 trillion ways. The variability is created
as
the genetic instructions for the predator protein are being
copied. Unique characteristics of the DNA sequence at these
12 sites
causes a “hiccup” in the copying process.
As a result, different amino acids—protein building blocks—end
up at the sites, and
a phage protein with different structural
and chemical properties is created.
“If we can learn from these organisms how
to set up a system that churns out proteins with enormous variability,
it may be possible
to target these new proteins
to specific cells to treat disease,” says Stephen McMahon,
a former postdoctoral fellow working with Ghosh.
That idea also excites the biotech
industry because it offers a new way to generate therapeutic
enzymes, vaccines and other medically important proteins.  —Sherry Seethaler
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