International team is
first to describe key protein interaction seen in muscles, cells
August 4, 2008
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Howard
White, Ph.D., in his lab. |
NORFOLK, VA —
Researchers from EVMS, the National Institutes of Health and the
National Institute for Medical Research in London have become the first
to describe in detail a key interaction in the function of a protein
vital to muscle contraction and the health of virtually every tissue and
cell in the body.
The study — “Direct observation of the mechanochemical coupling in myosinV
during processive movement” — was published in the July 30 issue of the
premier scientific journal Nature. The protein myosin is the central
component in the contraction of muscle and in the movement of subcellular components that are required for normal development and
function of most tissue and cells.
Although the research is very basic, the findings have important
implications for understanding the function and regulation of myosin and
its role in human health and disease.
Myosin accounts for almost half of the protein in muscle. It acts in
concert with the protein actin to produce movement and do work in
muscle, said
Howard White, Ph.D., EVMS professor of physiological
sciences. The fuel source for muscles is a molecule called ATP, a
product of food digestion.
“Scientists have been studying the anatomy and physiology of muscle for
more than 100 years but the details at a molecular level of how actin
and myosin use ATP to enable muscle to contract are now becoming
understood at an increasingly sophisticated level,” said White,
whose co-authors include Eva Forgacs, Ph.D., EVMS assistant professor of
physiological sciences.
Of the 40 types of myosin in the human genome, 10 are found in muscle
while the remainder are involved in various cell functions, most of
which are yet to be identified.
MyosinV is one of the non-muscle myosins that is that is present in high
concentration in the brain but has such diverse functions as
transporting the pigment that produces the color in our hair.
“Somewhat ironically, studying the non-muscle myosin has taught us more
about the molecular details of how myosin works than was learned from
studying muscle myosin,” White said. “This is because the non-muscle myosins often function as
single molecules to move their cargo, whereas millions of myosin molecules in muscle function as a large unit
in concert.”
The development of single molecule biophysical methods has enabled
scientists to study single myosin molecules. White likens the research
to learning about how a car engine works.
“You could learn something by watching how traffic moved and noting that
cars occasionally stop at a gas station, but you would learn a lot more
by taking a single car and opening up the hood and taking apart the
engine,” he said. “This has been our approach.”
One of the things that makes myosinV easier to study is that it “walks”
along the actin, whereas muscle myosin molecules constantly jumps on and
off the actin.
White and his colleagues tagged the myosin and ATP with different
colored fluorescent labels so that they could track the position of each
as they move along the actin filament.
In earlier research using a tagged ATP molecule made by colleagues at
the National Institute for Medical Research in London, White and his
colleagues found that the tagged ATP had several additional useful
properties. First, it was 20 times brighter after it bound to myosin,
which enabled the researchers to see only the bound ATP and eliminate
interference from unbound ATP molecules. Muscle breaks down ATP into a
smaller molecule called ADP. The rate at which the ADP comes off the
myosin limits how fast the myosin moves, and that rate is much slower
for the tagged ADP than for the natural untagged ADP. This in turn slowed the
rate of movement of the myosin and made it much easier to follow. The
researchers then realized this was an ideal model for studying single
molecules of myosin.
“All myosin molecules have two heads that can bind to actin,” White
explained. “By separately tracking the positions of the tagged ATP bound
to the myosin and the position of the myosin, we were able to show that
each step of movement always required ADP to come off of the rear head
of the myosin without movement, which was followed by ATP binding to the
rear head that resulted in the myosin moving approximately one millionth
of an inch.”
ADP never came off the front head until a new ATP bound to the rear
head.
“We had evidence from previous studies … that this happened but it was
very exciting to observe it directly,” White said. “None of this would
have been possible without the outstanding group that has contributed to
my laboratory’s work at EVMS: Betty Belknap
and Suzanne Cartwright.”
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