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"If your hands are together, your arms operate as one unit," said Rice
co-author Kevin MacKenzie, demonstrating a swing with an imaginary
bat. "But when you bunt," he said, sliding one hand up into the
classic bunter's stance, "your arms operate independently, and that's
what we're seeing calmodulin do in this case."
Calmodulin is a vital biochemical player in life
forms that range from fungi to humans. Its utility lies in its ability
to pass on signals both outside and inside of cells. It does this by
carrying out one specialized function: it binds with calcium ions and
changes shape when it does so. As it changes shape, it grabs hold or
lets go of other proteins.
"Nature could have selected a system where each
protein bound calcium on its own, but instead it uses calmodulin for
that and then has calmodulin interact with the other proteins," said
MacKenzie, assistant professor of biochemistry and cell biology.
One of calmodulin's roles in muscle cells comes in
regulating the flow of calcium ions into the cell. When your nerve
sends a signal to your heart to beat or your arm to move, the signal
causes tiny compartments of calcium inside the muscle cells to open
briefly and release a burst of calcium ions that cause the muscle to
contract. Then, tiny pumps throughout the cell remove the calcium and
put it back in the compartments, causing the muscle to relax.
Calmodulin is known to grab hold of the valve on
the compartment that opens to release the burst of ions and closes
again when the compartment is being filled. This valve, known as the
ryanodine receptor, or RYR1, is almost 35 times larger than calmodulin,
and the team from Rice and UT-Houston used a combination of X-ray
crystallography and nuclear magnetic resonance (NMR) to determine the
precise structure or shape of calmodulin that binds to the receptor in
the presence of calcium.
"Though calmodulin is known to bind to lots of
different proteins, it usually grabs hold with both lobes or lets go
with both, depending upon whether calcium is around," MacKenzie said.
"With RYR1, calmodulin stays bound whether calcium's there or not, and
we think this two-handed grip could play a functional role, perhaps
allowing it to keep hold with one lobe at all times, but grabbing and
releasing with the other to help open or close the valve."
MacKenzie said the researchers confirmed
calmodulin's new grip using state-of-the-art techniques on the Gulf
Coast Consortia's (GCC) powerful 800 MHz NMR in Rice's Keck Hall.
MacKenzie believes the new grip plays a key role in allowing our
muscles to contract and relax quickly. He said the team hopes to learn
more through follow-up investigations of the structure of calmodulin
that is bound to the receptor in the absence of calcium. Preliminary
results suggest that calmodulin uses yet another grip in this
situation.
"The combination of X-ray crystallography and NMR
residual dipolar couplings allowed us to identify both the overall
structure of the complex and movements within the complex on the
microsecond time-scale, which is important because that time scale is
relevant for fast-twitching muscles," he said. "But it's actually
pretty hard to measure motion at the microsecond time scale using
NMR." |
