NSF PR 96-66 - October 30, 1996
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Fertilization Protein Structure to Aid in Leukemia
Treatment
The structure of a protein recently discovered by
C. D. Stout at the Scripps Research Institute in La
Jolla, California, is providing insights into the
details of the interaction between sperm and egg.
Remarkably, the same structure may hold a key to new
treatments for leukemia, a kind of cancer that attacks
the blood.
The research, supported by the National Science Foundation,
has revealed a previously unknown relationship between
a protein in the eggs of a marine mollusk and a protein
on the outside of human white blood cells. The work
is published in the November issue of Nature
Structural Biology.
The egg protein is from the California sea snail,
Aplysia californica, an animal used by biologists
to study the process of fertilization. The details
of the events that occur at the molecular level when
a sperm cell joins with an egg are often the same
throughout the animal kingdom, including in humans.
One of the first events is that a flood of calcium
ions is released as a signal to the egg to prepare
to begin dividing. The flood of ions is controlled
by a regulatory molecule, a sort of molecular switch,
termed a secondary messenger.
The secondary messenger is synthesized inside the
egg from the building blocks of DNA. The synthesis
reaction requires a specialized protein, known as
ADP ribosyl cyclase. It is this protein that has been
studied by the researchers at Scripps. By preparing
crystals of the protein and scattering x-rays off
them, a three-dimensional image has been reconstructed.
The image reveals that two of the molecules combine
together to create a hole, or molecular cavity, between
the proteins. Inside this cavity the protein traps
the DNA building blocks and rearranges their pattern
of chemical bonds to synthesize the messenger.
In leukemia, white blood cells have a signaling protein,
called CD38, which in normal cells is only present
in early stages of their development. Because a CD38
molecule has a remarkable similarity to the cyclase
protein, Stout and his collaborators think that CD38
molecules also pair up to create an internal cavity.
However, unlike cyclase, CD38 has a tail reaching
across the cell membrane, providing a means for it
to transmit signals to the inside of white blood cells.
"By modifying the chemical bonds in molecules outside
the cell, the size and shape of the protein cavity
may be changed, and this effect can be transmitted
across the cell membrane by the attached tail," explains
Kamal Shukla, program director in NSF's division of
molecular and cellular biosciences, which funded Stout's
research.
The Scripps researchers hope that drugs targeted toward
the cavity in CD38 could be used to alter signal transmission
and allow the immune system to eliminate leukemia
cells.
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