The myosin superfamily
at a glance
M. Amanda Hartman1and James A.
Department of Biochemistry, Stanford University,
279 Campus Drive, Stanford, CA 94305, USA
*Author for correspondence (email@example.com)
Journal of Cell Science 125, 1627–1632
? 2012. Published by The Company of Biologists Ltd
The cytoskeleton is an interconnected
organization to cells. In eukaryotes, its
filaments. In addition to carrying out
structural roles, these filaments act as
tracks for the movement of molecular
motors that convert chemical energy into
mechanical work as they transport and/or
dynein motors both utilize microtubules for
transport, whereas myosins – which are the
focus of this Cell Science at a Glance article
– are the only known actin-based motor
proteins (Goode et al., 2000; Hartman et al.,
2011; Ross et al., 2008). Different members
of the myosin family are typically denoted
by roman numerals, such as myosin II and
myosin V; to ensure consistency between
the accompanying poster and the text, we
refer to them here as M2 (or class 2) and M5
(or class 5), respectively.
The myosin superfamily is a large and
diverse protein family, and its members,
which are grouped into many classes (Foth
2007), are involved in a number of
cellular pathways (Krendel and Mooseker,
2005; Woolner and Bement, 2009). We
mechanoenzymology and motility. Next,
we discuss myosin–cargo interactions and
present a summary of the roles of myosin
proteins in cells, focusing on actin-based
projections and the endomembrane system.
Finally, we provide an overview of the
diseases associated with myosin mutations
and our perspective on the future of the
myosin field. In order to provide a general
overview of the myosin family, we will not
be able to discuss some aspects of the vast
and important literature on myosins. For
example, we will not focus on the large
body of literature on yeast myosins, as it
deserves a rather long review on its own.
Myosins are mechanoenzymes
binding sites in their conserved catalytic
head domains. Conformational changes
(See poster insert)
Cell Science at a Glance1627
Journal of Cell Science
hydrolysis and product release are crucial for
the productive motility of myosin enzymes.
In the absence of nucleotide and in the ADP-
bound state, the head interacts strongly with
actin. By contrast, when ATP or ADP bound
to inorganic phosphate (ADP-Pi) bind to the
catalytic domain, the affinity of the myosin
head for actin is drastically lower. Thus,
association of myosin with its filamentous
track is regulated by the ATPase cycle.
Myosins vary in the rate at which they use
ATP and in how long per ATPase cycle they
are in the strongly bound state (duty ratio).
Some motor proteins, such as M2, have low
duty ratios, and each myosin head spends
little time in association with actin. Others,
such as M5, move processively for many
steps before detaching – a characteristic that
results from a high duty ratio (Howard,
Muscle and non-muscle M2, both of
which are the conventional members of
the myosin superfamily, form bipolar
unconventional myosins, such as M5,
have two heads and can take many steps
along an actin filament as a single
molecule. In these cases, the ATPase
cycles of the two identical heads are
staggered, such that at least one head is
strongly bound to actin at any time.
Following the binding of ATP, the rear
head dissociates from the filament, which
allows the front head to undergo a lever
arm swing, thereby propelling the rear
head forward. After the hydrolysis of ATP
and the release of phosphate, the former
rear head attaches to actin in its new front
position (De La Cruz and Ostap, 2004).
The changes in
are associated with large movements,
such as the 36-nm step taken by M5.
These movements are enabled by the
myosin lever arm, which amplifies the
conformational changes in the catalytic
domain to generate step sizes that directly
depend on the length of the lever arm. In
most myosins, the lever arm is a region of
the heavy chain to which one or more
calmodulin or calmodulin-like light chains
bind and provide
members of the myosin family, such as
M6 and M10, a single a-helix domain in
this neck region may also contribute to the
Myosins contribute to muscle contraction
The first myosin, M2, was discovered 1864
– in Heidelberg by Willy Ku ¨hne – in
muscle extracts (Ku ¨hne, 1864). We now
know how this muscle M2, which is
localized in the so-called muscle A-
bands, works. The conventional class 2
myosins have long coiled-coil domains
that allow multimerization to take place.
residues within these dimers mediate the
formation of bipolar thick filaments that
are responsible for contraction of muscle
filament consists of dozens of myosin
molecules that face opposite directions
from the midzone of the filament. In
muscle, these thick filaments are at the
center of the functional unit of the muscle,
the sarcomere. The sarcomere also consists
of two sets of actin filaments, which are
attached at their plus ends to structures at
the ends of the sarcomere called Z-lines.
All actin filaments are directed with their
minus ends toward the center of the
sarcomere. The thick myosin filaments
and thin actin filaments interdigitate and
interactions between the myosin heads
and the actin filaments, resulting in the
two Z-lines being pulled closer together.
Sarcomeres are attached to each other in
series by way of their Z-lines, and the
contraction of the sarcomeres, thus, leads
to contraction of the entire muscle.
Similarly, non-muscle M2 bipolar thick
filaments provide the force of contraction
needed to separate the two daughter cells
during cytokinesis (Vicente-Manzanares
et al., 2009). Additional myosins appear
to be involved in cell division; for
example, M6 participates in membrane
trafficking towards the cytokinetic furrow
(Arden et al., 2007). Other myosins
localize to the microtubule-based mitotic
spindle, which directs the position of the
cell division furrow. Human M10 and
Dictyostelium M1 have been shown to be
required for correct spindle formation
(Rump et al., 2011; Woolner et al.,
2008), and M5a has been found at
spindle poles, although its function at this
location remains unclear (Espreafico et al.,
1998; Wu et al., 1998).
Unconventional myosins associate
The diversity of the myosin superfamily
becomes particularly evident in the variety
of domains that are found in the C-terminal
tail of these proteins. Whereas the catalytic
elements, the tail regions of the various
(Thompson and Langford, 2002). The
unconventional myosins possess specific
domains in their tail regions that are
thought to enable their individual cellular
(Akhmanova and Hammer, 2010).
intracellular compartments and participate
in many trafficking and anchoring events.
The recruitment of motor proteins to an
organelle or molecular complex is generally
the result of the tail binding to a specific
adaptor protein. A number of myosin-
binding proteins have been discovered,
and their identities have often provided
understanding the cellular functions of
these motor proteins (Akhmanova and
Hammer, 2010). Most of these interactions
fall into one of several themes, which we
One of these themes is the connection
between myosins and members of the Rab
protein family through adaptor proteins.
For example, in melanocytes a complex
containing Rab27a, the adaptor protein
melanophilin and M5a is involved in
directed migration of pigment-containing
vesicles in these cells. Also, Rab27a, M7a-
and Rab-interacting protein (MyRIP) and
M7a have been shown to interact in retinal
pigment epithelial cells (Van Gele et al.,
Other myosins are involved in the
trafficking of cell surface receptors. For
example, M6 associates with the megalin
receptor through the adaptor protein GIPC
(GAIP interacting protein, C terminus)
and, thereby, permits correct targeting of
the receptor to the base of microvilli in
kidney proximal tubule cells (Naccache
et al., 2006). Representing another type of
interaction, many class 1 myosins directly
associate with lipids instead of binding
adaptor proteins, which allows them to
contrast, certain yeast class 1 myosins
have additional actin-binding sites in their
tails and contribute to filament nucleation
(Kim and Flavell, 2008).
Some myosins are thought to associate
with large protein complexes, such as
vertebrate M7a (Kussel-Andermann et al.,
2000) and Drosophila M6 (Finan et al.,
2011). In these examples, the myosin
Journal of Cell Science 125 (7)1628
Journal of Cell Science
potentially stabilizes its cargo in a certain
position or transport the complex to a
specific destination. Myosins are also
responsible for the directed movement of
ribonucleoprotein complexes, such as the
movement of protein-bound ASH1 mRNA,
which encodes a transcription factor that
newly budded daughter cell (Paquin and
Chartrand, 2008) by the yeast class 5
myosin Myo4p during budding division.
These examples are only a few of the
cargoes discovered for myosin proteins,
but many others fall into one of the six
myosin-binding proteins recruit myosins
to specific subcellular locations, they
enable these motors to associate with
organelle, vesicle or protein complex, the
motor protein can then exert its effects on
their movement or anchoring. Through
their specific interactions, myosins are
able to carry out a number of functions
in many different cell types, and their
importance is highlighted by their roles in
Myosins have roles in actin-based
Many myosins localize to membrane
microvilli, which are supported by large
actin bundles. Stereocilia are found in hair
cells of the inner ear and contribute to
auditory mechanotransduction. Microvilli
project from epithelial cells, including
those that line the intestines and ducts of
the kidneys; particular focus has been
placed on examining the roles of myosins
in the brush borders of the intestine and
kidney, which function in absorption. In
both types of structure, actin is oriented
such that the plus (barbed) end is at the
distal tip (Nambiar et al., 2010). Although
exception of M6 (Wells et al., 1999),
move towards the plus end, they are not
evenly distributed throughout stereocilia
and microvilli; their specific positions at,
for example, the base or tip of these
projections are likely to be a reflection of
their specific functions.
For example, M15a is found at the tip
of stereocilia (Belyantseva et al., 2003),
whereas M7a is present throughout the
length of the stereocilium and possibly
concentrated near its base (Hasson et al.,
1997; Senften et al., 2006). Each of these
two motors associates
Although M1c localizes along the length
of stereocilia (Schneider et al., 2006), it
concentrated, i.e. near the cilial tip links
– linkages connect neighboring stereocilia
and are perturbed by sound waves during
the hearing process (Gillespie and Cyr,
2004; Hasson et al., 1997; Steyger et al.,
1998). In addition, M7a was recently
identified as a component of the upper tip
link (Grati and Kachar, 2011). Both M6
and M7a are found below the base of
stereocilia (Hasson et al., 1997), and in the
case of M6, the myosin protein is thought
to ensure correct membrane tension that is
required for the maintenance of these
projections (Altman et al., 2004; Nambiar
concentrated below the tip (Schneider
transporting the actin-bundling protein
espin 1 away from the cell body to
ensure correct assembly and elongation of
actin (Salles et al., 2009).
Many of the myosins that are found in
stereocilia are also found in microvilli
ofthe brush border.
concentrated near the base, as are M5 and
M1d (Benesh et al., 2010; Heintzelman
et al., 1994). In addition to M5 and M7b,
M1d is also present in the tips of
microvilli, whereas M1a is present along
the entire length of the microvillus (Benesh
et al., 2010; Heintzelman et al., 1994).
Although the specific functions of each
myosin in these projections are less clear
than in, for example, stereocilia, they
might carry out essential functions in the
regulation of actin structure and general
cilia organization. Interestingly, it was
essential for the shedding of vesicles
from microvilli (McConnell et al., 2009;
participate in membrane trafficking in
cells containing these structures. Indeed,
many myosins have been connected to a
variety of membrane compartments.
Myosins organize the endomembrane
Myosins can be found in nearly any
cellular location, where they are thought
to link each cargo to the actin cytoskeleton
example, type 1 and 6 myosins are
associated with endocytic vesicles and
endosomes (Chen et al., 2007; Hasson,
2003; Krendel et al., 2007; Puri et al.,
2010; Raposo et al., 1999; Salas-Cortes
et al., 2005; Wang et al., 2008) and M5b
compartments (Wang et al., 2008). Both
M1b and M7a have been found on
lysosomal membranes (Raposo et al.,
1999; Soni et al., 2005). By contrast, M10,
Tetrahymena M14, and Dictyostelium M1
and M7 associate with phagocytic cups or
phagosomes (Cox et al., 2002; Hosein and
Gavin, 2007; Rump et al., 2011; Tuxworth
et al., 2001). In addition, M5a and M5c
contribute to the exocytosis of dense-
respectively (Jacobs et al., 2009; Varadi
et al., 2005).
Other types of myosin involved in
secretion include M1b, M6 and M18a,
each of which is found on the Golgi
complex (Almeida et al., 2011; Dippold
et al., 2009; Spudich and Sivaramakrishnan,
2010). M5a probably
peripheral endoplasmic reticulum (ER) to
dendritic spines in neuronal cells (Wagner
etal., 2011). M9b andmany class 1 myosins
(McConnell and Tyska, 2010; van den
Boom et al., 2007), and M6 and M18a are
found in membrane ruffles (Buss et al.,
1998; Hsu et al., 2010). Mammalian M10
filopodia, which are cellular extensions
that are often found at the leading edge of
filopodial formation, M15 is thought to
carry out filopodial transport (Berg and
Cheney, 2002; Liu et al., 2008).
mitochondria in human cells (Quintero
et al., 2009), whereas in maize it seems to
be M11 (Wang and Pesacreta, 2004). In
Arabidopsis, M8 and M11 are responsible
organelles and are found, for example, on
the Golgi, ER and plasma membrane
(Sparkes, 2010). In addition, although
myosins are generally restricted to the
cytoplasm, members of several classes,
including M1c, M6 and M16b, have been
found in the nucleus and might function
there (Woolner and Bement, 2009).
The locations of myosins presented
here are certainly not comprehensive, and
future work is essential to fully define
the subcellular localizations and cargo
complexes of myosin motor proteins.
unconventional members, M2 has also
been implicated in numerous functions
Journal of Cell Science 125 (7) 1629
Journal of Cell Science
beyond muscle contraction and cytokinesis,
such as cell adhesion, rearrangement and
cell polarity (Vicente-Manzanares et al.,
2009). Determining the extent to which
myosins and other motor proteins cooperate
to organize cellular contents is an emerging
area of research, which may progress further
by deducing the phenotypes associated with
Mutations in myosins can cause disease
Numerous myosin mutations have been
syndromes (Table 1), and myosins are
necessary for the process of hearing
through their contribution to the structure
of to stereocilia (Nambiar et al., 2010).
Mutations in M7a can lead to non-
syndromic deafness or Usher syndrome,
the leading cause of genetic deaf-blindness
(Kremer et al., 2006). M5b might transport
apical endosomes in brush border cells
(Szperl et al., 2011), which could explain
the association of mutations in this gene
with microvillus inclusion disease (Muller
et al., 2008). Furthermore, mutations in
M5a are linked to Griscelli syndrome,
which is characterized by defects in
pigmentation and neuronal malfunction
(Van Gele et al., 2009).
Because class 2 myosins are essential for
muscle contraction, cell division and other
fundamental processes, mutations in the
genes encoding these proteins can lead to
severe forms of disease. For example,
cardiomyopathies, which are characterized
(Walsh etal.,2010).M6 and M18b havealso
been linked to heart defects, although the
molecular basis for these phenotypes is not
known (Ajima et al., 2008; Mohiddin et al.,
2004). Furthermore, it is unclear what the
specific roles for Drosophila M1 and mouse
M9a are, whose disruption leads to reversal
respectively (Abouhamed et al., 2009;
Hozumi et al., 2006; Speder et al., 2006).
Although M9b has been linked to a
number of intestinal disease states, there is
associations. Two studies implicated this
motor protein in celiac disease (Monsuur,
2005; Wolters, 2007), but other data
indicate that this association is absent in
a number of populations (Hunt, 2006;
Amundsen, 2006a; Nunez, 2006; Cirillo,
inflammatory bowel diseases (Latiano,
2008; Nunez, 2007; van Bodegraven,
2006; Cooney, 2009), this might not be
the case for all cohorts (Amundsen,
2006b), which adds to the debate about
the function of this motor protein.
over these genetic
The molecular basis of energy transduction
reasonably well understood after decades of
research using many different approaches.
Similarly, the cellular functions of M2 in
muscle contraction and cytokinesis can be
fairly well described at the molecular level.
The cellular roles of other members of
the myosin family are beginning to be
elucidated,butthereisstillmuch work todo
in this fruitful research area. It is clear that
the ,40 different myosins in a particular
cell type are involved in setting up the
dynamic layout of the cell. However, the
multitude of cargo-binding, structural and
regulatory elements that must exist to direct
the numerous myosin motor proteins to
carry out their various functions inside the
cell have not yet been identified and
characterized. The field is at the tip of an
iceberg with respect to such much-needed
biochemical studies, and future research
should certainly consider cargo-binding
elements of molecular motors as one of
the upcoming frontiers in the research of
The time is also ripe to focus on the
clinical ramifications of alterations to the
actin–myosin contractile system associated
with particular disease states. A classic
example is the hundreds of sarcomeric
protein mutations that, individually, lead to
hypertrophic or dilated cardiomyopathy –
debilitating diseases that can lead to
sudden death. These days, the connection
between basic research and its application
in the treatment of diseases is much easier
to forge in this modern era of genomic
biology – and the biotech world is not far
directly targets b-cardiac myosin has
recently been reported as a potential
treatment for congestive heart failure
(Malik et al., 2011), a prevalent disease
approaches. The next decade will see
much more activity
approaches to the myosin family of
This work was supported by the National
GM33289 to J.A.S.]; a Human Frontiers
Table 1. Phenotypes associated with myosin mutations
MyosinOrganism Phenotype Reference
M31DF (class 1)
Cardiac muscle M2
Cardiac muscle M2
Crinkled (class 7 myosin)
Microvillus inclusion disease
(Donaudy et al., 2003)
(Zadro et al., 2009)
(Hozumi et al., 2006; Speder et al., 2006)
(Walsh et al., 2010)
(Walsh et al., 2010)
(Kunishima and Saito, 2010)
(Kunishima and Saito, 2010)
(Walsh et al., 2002)
(Van Gele et al., 2009)
(Muller et al., 2008)
(Melchionda et al., 2001)
(Mohiddin et al., 2004)
(Kremer et al., 2006)
(Liu et al., 1997)
(Todi et al., 2005)
(Abouhamed et al., 2009)
(Wang et al., 1998)
(Ajima et al., 2008)
Journal of Cell Science 125 (7)1630
Journal of Cell Science
National Institutes of Health Cell and
Molecular Biology Training [grant number
T32GM007276 to M.A.H,]; and a Stanford
Graduate Fellowship awarded to M.A.H.
Deposited in PMC for release after 12
A high-resolution version of the poster is available for
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