Dynamic Actin
By Jason Socrates
Bardi
MIRANDA:
O, wonder! How many goodly creatures are there here! How
beauteous mankind is! O brave new world, That has such people
in it!
———William Shakespeare, "The Tempest," 1611.
Some of the most exciting areas of research are those dynamic
ones in which we are just embarking. Velia Fowler, who is
a professor in the Department of Cell Biology, has spent several
years studying how actin filaments work to stabilize the shape
of a cell, and how actin filament organization is controlled
by actin binding proteins.
"[I've been] interested in how the cell regulates actin
polymerization and generates specific actin architectures
in different cells," says Fowler.
Now Fowler will be pursuing a whole new direction in her
research—investigating the dynamic properties of actin
and how cells control the polymerization of actin to control
cell motility, shape changing, crawling, and phagocytosis.
Muscles of Steel
Actin is a structural protein that forms filaments made
up of monomers added one onto the other, and actin bundles
or networks are groups of these fibers bound together with
other proteins. Like the steel girders that stabilize a building
beneath the glass and mortar, the different arrangements of
actin filaments into bundles or networks are the supporting
structures that give cells different morphologies, or shapes.
These shapes go hand and hand with the functional properties
of the cell, and an important part of development is the formation
of the correct actin cytoskeleton.
"The form is designed for the function, and it's dependent
on actin polymerization and the integration of actin filaments
into higher-order structures," says Fowler.
Epithelial cells that line the intestines have long, finger-like
projections into the intestine supported by bundles of actin
filaments that increase the surface area of the intestinal
lining. This improves the absorption of nutrients that are
then transported through the blood stream.
Red blood cells, which are responsible for transporting
oxygen through the bloodstream, have a two-dimensional network
of short filaments of actin connected by linker proteins that
give the cells their flattened, biconcave disc shape. This
network is flexible and can be distorted so that a red blood
cell can squeeze through capillaries one fourth their size.
Actin also plays a key role in the physiology of muscles.
Heart and skeletal muscle cells have parallel bundles of actin
filaments arranged end-to-end in long strings of regular repeating
units called sarcomeres. In these sarcomeres, bipolar filaments
of myosin, another protein fiber in muscles, pull on the opposing
sets of actin filaments from each end to shorten the sarcomeres.
This generates muscle contractions that powers the beating
of the heart and movements of skeletal muscles. Remarkably,
the lengths of the actin filaments in the muscle sarcomeres
are held constant and do not vary over many cycles of contraction.
However, mechanical stress and other environmental cues
influence this length.
For example, actin filament lengths in sarcomeres vary between
fast and slow twitch skeletal muscles. Different muscle groups
in the body have different combinations of fast and slow twitch
muscles, and in athletes, the combination is largely determined
by the type of training that they do. Long distance runners,
for instance, have a different combination than sprinters.
And if a runner were to switch from 100-yard dashes to marathons,
his/her muscle groups would slowly adapt to the new demands.
"When you think of architecture, you think of something
stable, fixed—a defined form," says Fowler. And even
though cells have apparently stable actin filaments, they
are not like steel girders—formed once and fixed in their
shape. Instead, there are cycles of polymerization used by
the cell to create structures and change their length as opposed
to making completely new ones from scratch.
"Cells need to be plastic," she says. "They have to change
in time and respond to physiological conditions."
This Candle Burns at Both Ends
Fowler is interested in what controls the length of an actin
filament. She uses muscle cells to study the dynamics of actin
filaments, since actin filaments in muscle are about one micron
long, which can easily be viewed with a light microscope.
"We can study the dynamics of actin in muscles—the engine
that leads to the contraction—and we can study it as
it happens," she says.
To do this, Fowler's research focuses on a protein that
caps one end of the actin filaments and controls their length
by controlling the subunit exchange of bound and free actin
subunits.
Actin filaments are polarized, and the two ends are dissimilar
both in terms of their appearance under a microscope and the
types of other proteins that they bind to. The "barbed" end
is where much of the subunit exchange takes place and where
many different types of capping proteins, one of which was
identified in the Fowler laboratory, exist to regulate this
exchange. But the other, "pointed," end is what particularly
holds Fowler's interest.
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