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Introduction: the
mechano-biochemistry of
molecular motors
Rob Cross
Molecular Motors Group, Marie Curie Research Institute, Oxted,
Surrey RH8 OTE, U.K.
Molecular motors are mechano-enzymes, protein machines for transducing
chemical potential energy into mechanical motion. Some general principles of
their mechanisms are known from now-classical biochemical and physiological
studies on muscle. The catalytic cleavage of a nucleotide (usually ATP) in the
active site drives the motor into a metastable, mechanically strained
conformation, and the subsequent relaxation of this conformation to an
unstrained state is harnessed to do useful work. To gain more detailed
information about structure–function relationships we need to tinker with
each motor, much as a motor mechanic tinkers with a macroscopic engine. The
questions are the same. What moves? Why does it move? What limits its
performance? What happens when I pull this?
Like the motor in your car, molecular motors have an operational cycle of
forceful shape changes, and again like your car, this cycle is co-ordinated and
driven by the chemistry of fuel consumption. For molecular-scale motors, it is
the chemical catalytic cycle of ATP turnover in the motor active site that drives the development of mechanical strain. And just as the chemical transitions
of ATP processing generate motion, so mechanical strain applied to the motor
by an external load can feed back on the chemistry of the motor active site.
This feedback allows the motor not only to generate force, but also to collaborate efficiently with other members of a team of motors. By sensing the forces
produced by its team mates and adjusting its own force-generating schedule to
fit in, a particular motor can contribute efficiently to a team effort. The prob-
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Essays in Biochemistry volume 35 2000
lem, which we have with each molecular motor, is to understand the system of
mechanical linkages, levers, springs, pressure plates, push-rods, bearings and
even axles that amplify slight motions in the catalytic residues into larger-scale
motions of the full molecule. The study of this reciprocal mechanochemical
coupling is the linking theme of the essays in this volume.
Most of the setting up and maintenance of the large-scale organization in
living cells relies on an interplay between motor-driven transport of components along cytoskeletal tracks (actin filaments and microtubules), and the
(partly motor-dependent) continuous re-organization of cytoskeletal track.
The classical motor is myosin II, the engine for skeletal-muscle contraction
(Bagshaw) and also for smooth-muscle and cardiac-muscle contraction
(Davison, D’Cruz and McKenna). More recent studies have revealed a plethora of previously unknown isoforms of myosin (Kalhammer and Bahler),
kinesin (Kull) and dynein (Harrison and King), each specialized for a particular mechanical task. Critically, motor-dependent processes include mitosis and
cytokinesis, the morphogenesis of the endoplasmic reticulum, the directional
transport of Golgi, lysosomes and chloroplasts; exo-, endo- and pinocytosis,
the polarization of the egg, gastrulation, cell crawling, muscle contraction
(Bagshaw), the beating of cilia and flagella (Woolley), the actuation of hearing
(Libby and Steel), and even thought itself [neuronal growth-cone motility and
the axonal transport of neuortransmitter-containing vesicles (Signor and
Scholey)]. Together, the track-following molecular motors kinesin, myosin
and dynein are responsible not only for the transport and targetting of cellular
components, but also for tensioning, sliding and rearranging cellular arrays of
microtubules and actin filaments, and even governing their rates of assembly
and disassembly. With only a modest leap of the imagination, even the bacterial rotary motors and and the bacterial F1-ATPase (Kinosita, Yasuda and Noji)
can be regarded as following an endless, circular track. The problem of the
stepping mechanism by which the motor moves along its track is thus in common between muscle and non-muscle myosins, kinesin, dyneins, DNA-track
followers (Szczelkun) and the GTPase mRNA-track follower elongation factor G (Wintermeyer and Rodnina). Solving this central problem is a demanding task, but the field has an enviable record of experimental ingenuity, including the development of entirely new types of single-molecule microscope
(Knight and Molloy; Kinosita et al.), and there is every prospect of success.
The scientific study of the best-understood motor, myosin, can be traced back
400 years to the Renaissance, but far from senescing, our field has not yet even
reached maturity. What we are set to learn will have wide implications for
biology, where the mechanical aspect of biochemical reactions is underappreciated, and, beyond that, for nanotechnology and molecular-scale robotics.