Stanford Report, February 28, 2001
|New studies shed light on
how a family of molecular motors move
BY CHARLES CLAWSON
Stanford medical researchers have discovered how tiny molecular motors known as myosins move and how that motion is fueled within a cell during cell division -- an understanding that may open a gateway for molecular research of cancer and other diseases.
"To understand how these protein motors 'burn' their fuel and convert that to mechanical motion is fundamental because movement is nearly the definition of life," said James Spudich, PhD, professor of biochemistry and of developmental biology and the Douglas M. and Nola Leishman Professor of Cardiovascular Disease. "Every organism involves some kind of movement, and movement most often is driven by molecular machines."
Every cell in our bodies contains about 100 different proteins that act like motors in carrying out various forms of movement. One family of motors, myosins, is responsible for much of our movement -- from slam dunks to heartbeats to cellular growth. Myosins exist in a wide spectrum of shapes and sizes but all function by transforming chemical energy into movement along molecular tracks known as actins. A recent study by Spudich and two Stanford colleagues focuses on myosin-II, the motors that drive such functions as muscle contraction and cell division.
"The molecular motors walk along these actin tracks much like a person walks -- bending at the knee, planting the foot on the ground (attaching to actin) and then straightening the leg to pull the body forward in following a one-way track," said Spudich. This motion, central to muscle contraction and cell division, occurs when the cell's fuel, known as adenosine triphosphate or ATP, is broken down into adenosine diphosphate and one phosphate molecule. The resulting chemical energy is transformed into mechanical motion.
This knowledge is fundamental to understanding how our bodies operate because cells replenish by dividing and forming new cells. When the cell division process goes awry, the result can be diseases such as cancer.
Additionally, understanding myosin-II's role in the contraction of heart muscle could provide significant insights into hypertrophic cardiomyopathy, a disease linked to genetic mutations in myosin motors that can result in sudden death. Many such cases -- like those involving seemingly healthy athletes who die during physical activity -- have been traced to defects in the cardiac myosin molecule.
In the study, Spudich and his colleagues developed a model cell system using Dictyostelium, a cellular slime mold similar to a yeast or fungus. Dictyostelium behaves much like human cells but is easier to manipulate. Using genetic tools, the researchers disabled myosin-II in the cells and found they were unable to divide properly.
"Dictyostelium cell division uses the same myosin-based machinery that our muscles use," said Spudich. "The actin in our muscle is 95 percent identical to the Dictyostelium actin, and the two myosins are essentially identical in structure."
"Your heart is mostly muscle, driven by contractions of this actin and myosin machine," Spudich added. "The way the heart mechanically contracts is closely related to the way cell division occurs in Dictyostelium. In a non-muscle cell the contraction causes the cell to divide into two. In heart muscle the same kind of mechanism causes the whole heart to contract and relax."
The results of the myosin-II study are being published in the March issue of Nature Cell Biology. Spudich's collaborators are Coleen Murphy, PhD, and Ronald Rock, a postdoctoral fellow. The paper addresses how the breakdown of ATP fuels the mechanical motion of myosin. A particular mutant form of the myosin is shown to have kinetic and mechanical defects that cause the uncoupling of the ATP breakdown from the mechanical motion.
That paper joins two other recent papers co-authored by Spudich that examine myosin motors. The three linked studies are notable for the broad spectrum of their approaches. "To understand something as complex as this we used a multidisciplinary approach including physics, genetics and biochemistry," said Spudich, head of Stanford's Bio-X program, which promotes interaction between engineering, medicine and biosciences. "When scientists bring together their different technologies to solve problems, fascinating things can happen."
first paper, published Aug. 15, 2000, in Proceedings of the
National Academy of Sciences uses biophysical approaches to follow
the stepping of a single myosin molecule along a single actin
track. The second paper, published Sept. 1, 2000, in Cell uses
another biophysical approach to meter the conformational changes in
the myosin that drives the mechanical movement of the actin
filament. All three studies were funded by the National Institutes