Keywords: Myosin I; Myosin
II; Myosin V; Myosins VI,VII, XV; Plant Myosins VIII, XI, XIII.
Myosins A superfamily of molecular motor proteins (17 classes identified so far) present in probably all eukaryotic cells. Bind to actin and use the energy of ATP hydrolysis to generate force and movement along actin filaments. The motor proteins involved in muscular contraction, cytokinesis, short-range membrane/vesicle transport and a host of other cellular processes.
Actins Highly conserved proteins present in all eukaryotic cells. Exist in a dynamic equilibrium between monomer and filament states controlled by interacting proteins. Form the microfilament component of the cytoskeleton, thin filaments in muscle and the scaffold to which a multitude of proteins bind.
Kinesins Exist as a superfamily of molecular motor proteins in most if not all eukaryotic cells. Associate with microtubules and hydrolyse ATP to produce force and movement along microtubules. Motor proteins involved in mitosis, long range vesicle transport and a multitude of other cellular activities.
Myosins are a large family of
actin-based mechanoenzymes that bind and hydrolyse ATP to generate
the force and movement along actin filaments necessary to drive
a wide variety of cellular functions (Mooseker & Cheney, 1996;
Cope et al, 1996; Sellers 1999). Phylogenetic analysis
has so far identified seventeen distinct classes of myosin (designated
I to XVII) (see Figure 1).
Click here for updated Tree as found on the Myosin Web Page
Figure 1: An Unrooted Phylogenetic Tree of the Myosin Superfamily
The tree is derived from an alignment of 145 members of the myosin superfamily. This alignment compares the core motor domains (equivalent to amino acids 88 to 780 of chicken skeletal myosin II -see Cope et al, 1996) of each myosin using distance matrix analysis performed with the Clustal-W package. The exceptions, shown with a dotted line, are SsVIIa, a partial sequence in the databases and Hs MysPDZ, which has a truncated amino end starting some 52 residues into the core motor region. Gap positions in the alignment were included during bootstrap analysis (repeated redrawing of the tree structure to yield confidence estimates) in order not to exclude a large proportion of the data. Being unrooted, the relationships between classes as shown by the branching order at the centre of the tree are unreliable but evolutionary information can be derived within a class. The molecular cartoons serve to indicate possible molecular structure, especially the expected single or double headed nature of the myosins.
Cell movement, muscular contraction, cytokinesis, membrane trafficking and signal transduction are driven by myosins that move unidirectionally along actin filaments (Mermall et al, 1998; Baker & Titus,1998). Most of our knowledge about the structure, mechanism and properties of myosins has been gained by work on 'conventional' (muscle type) myosin II. Apart from the myosins in classes I and V rather little is known about the properties of the other classes of myosins; most of our information is at the DNA level.
All myosins are composed of three functional domains (see Figure 2):
Figure 2: Myosin Domain Structure as Predicted from Sequence Analysis.
The predicted functional domains identified in the various myosin classes are shown graphically for representatives of each class. The protein sequence bars and domain sizes are only approximately to scale; hence no scale is given. Note the motor domains are relatively conserved whereas the tail domains are highly variable.
1) a motor region (head) whose core sequence is highly conserved in all the myosin classes. Structures of this region from various myosin IIs have been determined. They show a core motor (catalytic) domain with a relatively open ATP binding pocket and an actin binding interface followed by a 'converter' region which links the core motor domain to the 'lever arm' (Rayment et al, 1993; Dominguez et al, 1998; Houdusse et al, 1999). The core motor structure is similar to that in the kinesins, the microtubule-based motors, implying that a common ATP dependent conformational change mechanism is used to generate motion by these motor proteins (Vale & Milligan, 2000);
2) a neck region (or 'lever arm') composed of a long helix of variable length depending on the number of IQ motifs (from none to six) which have the consensus sequence (IQxxxRGxxxR) and bind either light chains or calmodulin. So far the only class of myosin which lacks such a neck region is the class XIV Toxoplasma myosin A (Heintzelman & Schwartzman, 1997);
3) a tail region which is extremely variable in sequence length, domain composition and organisation (see Figure 2). Although the identity and role(s) of many of the tail domains have yet to be established, they are believed to be involved in determining the cellular localisation (targeting) and function of the myosin (e.g. filament assembly, cargo binding). Myosins with tail regions containing predicted a-helical coiled coil domains are believed to be dimeric with two motor domains whereas those without a coiled coil region are monomeric with a single motor domain.
Phylogenetic analysis based on a comparison of their motor domain sequences has divided the myosins into seventeen classes (see Figure 1). A similar classification would be obtained if the tail domain sequences were compared. Mammalian cells contain the largest number of myosin genes (so far 28 myosin genes have been identified belonging to the following nine classes I, II, III, V, VI, VII, IX, X and XV) (Sellers, 2000). The genome of the yeast, Saccharomyces cerevisiae, has now been sequenced and it contains just 5 myosin genes (two class I, one class II and two class V myosins) (Brown, 1997). In the nematode, Caenorhabditis elegans, whose genome sequence is almost complete, 14 myosin genes have so far been identified (two class I, six class II, one class V, two class VI, one class VII, one class IX and one class XII myosins) (Baker & Titus, 1997). The myosin genes in classes VIII, XI and XIII are expressed exclusively in plants and of the 26 genes so far identified 16 are found in Arabidopsis thaliana (Reichelt & Kendrick-Jones, 2000).
More information on the myosins, together with an alignment of 145 myosin motor domains and links to the sequences available at http://www.mrc-lmb.cam.ac.uk/myosin/myosin.html
Myosin II (the conventional myosins)
At least one myosin II gene has been identified in all eukaryotic cells examined except those of plants. On the basis of their motor domain (or tail) sequences (Figure 1) the myosin IIs can be divided into four groups or types: 1) skeletal/cardiac muscle (sarcomeric) myosins; 2) vertebrate smooth muscle/nonmuscle myosins; 3) Dictyostelium /Acanthamoeba type myosins; 4) yeast type myosins (very little is known about these myosins at the protein level). The characteristic feature of these myosins are their a helical coiled coil tails that self assemble to form a variety of filament structures (bipolar or side polar filaments) that are essential for their function. Vertebrate striated muscle myosin II is discussed in detail in section. and has been extensively reviewed (see Cooke, 1997). In comparison much less is known about the other groups of myosin IIs.
Myosin IIs are dimeric with two heavy chains of 170-240kDa and two pairs of light chains (16-23kDa) called the essential (ELC) and regulatory light chains (RLC) which stabilise the long helix in the neck region that forms the 'lever arm'. The structures of the myosin II motor domain reveal a core catalytic domain followed by a 'converter' region linked to the rigid 'lever arm' domain (~8nm in length) (Rayment et al, 1993). Structural studies suggest a model whereby ATP induced changes in the core catalytic domain (when attached to actin) are transmitted to the converter and lever arm domains causing them to rotate relative to the catalytic domain. This causes the myosin to move along the actin filament by the angular rotation of its lever arm (Holmes, 1997; Houdusse et al, 1999).
Myosin II interaction with actin
filaments is regulated by four distinct mechanisms;
1) in vertebrate smooth muscle/non-muscle myosin IIs, phosphorylation
of the RLC by a calcium/calmodulin dependent light chain kinase
switches on myosin-actin interaction (Tan et al, 1992;
Bresnick, 1999). RLC phosphorylation also regulates the ability
of these myosins to assemble into filaments;
2) although vertebrate striated/cardiac muscle myosin RLCs are
phosphorylated by a similar kinase, regulation in these muscles
is controlled by the troponin/tropomyosin complex on the actin
filaments (Farah & Reinach, 1995);
3) in molluscan muscles, myosin-actin interaction is regulated
by direct calcium binding to the myosin ELC (Xie et al
1994), whereas
4) in Acanthamoeba and Dictyostelium myosins, phosphorylation
at distinct sites in their heavy chain tails inhibits their interactions
with actin (Tan et al, 1992). RLC phosphorylation may have
an additional regulatory role in these myosins.
Molecular genetic studies in Dictyostelium, C.elegans, Drosophila and yeast (especially using genetic manipulations such as gene 'knock-outs') (see review by Sellers, 2000) have indicated that in addition to its well characterised role in contraction and force production in skeletal, cardiac and smooth muscles (discussed in section .) myosin II is required for cytokinesis, cell motility, cell polarity/chemotaxis, maintaining cell architecture and development in nonmuscle cells.
Myosin I was the first unconventional
myosin to be discovered (Pollard and Korn, 1973). It was notable
for being a single headed myosin and unable to self-associate
into bipolar filaments. Based on phylogenetic analysis of their
motor domains, myosin Is have been divided into four subclasses
(Figure 1) (see reviews by Coluccio,
1997; Barylko et al, 2000). They are described here in
order of the discovery of the founding member for each subclass.
An alternative nomenclature is also shown with the myosins from
Rattus norvegicus (myr, myosin from rat)
as examples.
Subclass 1 (subclass C, myr3)
Also called amoeboid myosins
following their initial discovery in Acanthamoeba and Dictyostelium
but have now been identified in Saccharaomyces and
Emiricella (Aspergillus) and vertebrates (chicken,
mouse, rat and human) (Mooseker & Cheney, 1995; Coluccio,
1997). They contain a single motor domain followed by a neck region
consisting of one or two IQ motifs which bind calmodulin-like
subunits and a tail region containing from one to three Tail Homology
Domains (TH1-3). The long tailed isoforms contain TH1 which is
rich in basic residues and lies adjacent to the neck; this is
followed by the TH2 or GPA/GPQ domain rich in glycine, proline
and either alanine or glutamine and capable of binding actin in
an ATP-insensitive manner (giving these myosins two potential
actin-binding sites) and the TH3 domain which has SH3 homology
(Pollard et al, 1991). Short tailed isoforms contain only
TH1. Roles for subclass 1 myosins include cell crawling, chemotaxis,
phagocytosis, pseudopod extension and contactile vacuole function
(Wu et al, 2000). Mutations and gene knockout experiments
on the three subclass 1 myosins in Dictyostelium have shown
that they have both shared and distinct functions (Jung et
al, 1996).
Subclass 2 (subclass a, myr1)
Members of this subclass have been identified in Dictyostelium
and vertebrates where they are extensively expressed with
the highest levels in gut, brain, lung, kidney and liver (Mooseker
and Cheney, 1995). They contain a neck region with 3-6 IQ calmodulin
binding motifs and a tail domain (TH1) rich in basic residues
believed to be responsible for their localisation to microvilli
in the case of brush border myosin I. Here they act as cross-links
between the membrane and actin filament bundles. Myr 1 expressed
in non-polarised cells, is enriched in the cleavage furrow during
cell division and in cell protrusions and membrane ruffles at
the plasma membrane (Ruppert et al, 1995).
Subclass 3 (subclass b, myr2)
These myosins were first detected in vertebrates and then
in Drosphila and frog and contain a neck domain
with 3 IQ motifs and a tail region (TH1) rich in basic residues
which can bind phospolipids. (Wagner et al, 1992). They
have a broad range of tissue expression with the highest levels
in spleen, heart, lung, adrenal gland, oesophagus and stomach.
They have been shown to be associated with actin rich structures
in ruffles and protrusions in the plasma membrane in cultured
neurons (Barylko et al, 2000). Frog myosin Ib is localised
to the sensory hair cells of the frog sacculus where it may modulate
the sensitivity of the hair cell bundle to mechanical stimulation
(Garcia et al, 1998).
Subclass 4 (subclass g, myr4)
The rat (myr4) and Drosphila myosin (Dm IA) are similar
with 2 IQ motifs in their neck regions and tail regions containing
one TH1 domain rich in basic and hydrophobic residues (Bahler
et al; 1994). Myr4 has a wide range of tissue expression
with the highest level in the adult brain localised to a subset
of neurons whereas Dm IA is exclusively expressed in the gut epithelia
(Gillespie, et al 1993).
Although myosin Is are the largest single class of myosins so far identified most of their cellular functions remain to be determined. However there is evidence in yeast and mammalian cells that myosin Is are particular important in the endocytic pathway and can be localised to specialised compartments such as the recycling endosome or lysosome (Raposo et al, 1999). A number of myosin Is have been shown to be regulated either by heavy chain phosphorylation by specific kinases or by calcium binding to calmodulin in the neck region or possibly by tail domain targeting to specific receptors (see review by Barylko et al, 2000). However very little is known about their regulation at the cellular level.
Myosin III , named ninaC (neither inactivation nor after potential C) was first discovered in Drosophila eye as a gene behind a phototransduction defect (Montell and Rubin 1988) and has now also been identified in horseshoe crabs, fish and humans (Battelle et al, 1998; Hillman et al, 1996). NinaC is monomeric and differs from all other myosins in having an N terminal kinase domain and serves as a link between the cytoskeleton and the signaling complex involved in phototransduction. Two splice variants exist in the Drosophila eye; p174 (a phosphoprotein) has two IQ light chain binding motifs with a 420 amino acid tail which localises to the dense arrays of microvilli that make up the rhabdomere of the photoreceptor whereas p132 has a 54 amino acid tail with one IQ motif and localises to the photoreceptor cell body (Montell, 1999). Mutagenesis and binding studies have identified the regions of p174 that are important for localisation, termination of phototransduction and rhabdomere maintenance (Wes et al, 1999; Montell, 1999; Bahler, 2000). p132 does not appear to be essential for phototransduction (Montell, 1999).
Myosin IV has only been identified in Acanthamoeba (Horowitz & Hammer III, 1990). It is predicted to have a single motor domain, one IQ motif and a tail with a Myosin Tail Homology (myTH4) domain homologous to that in the tails of myosins VII and XV.
Myosin V is present in most if not all eukaryotes excluding plants (Titus, 1997; Reck-Peterson, et al, 2000). In vertebrates it exists in three distinct subclasses (myosin Va,b&c) which are differentially expressed but it is not known whether they have distinct or overlapping functions (Bement, et al, 1994; Wu et al, 2000). In yeast there are two subclasses, Myo2p and Myo4p, which have clearly different functions (Brown, 1997).
Myosin V is a dimeric molecule consisting of conserved motor domains followed by 6 IQ motifs which bind specific light chains and calmodulin (Espindola et al 1992; Reck-Peterson, et al, 2000). The tail domain is important for cellular localisation and cargo binding and can be divided into a a-helical coiled coil region which in vertebrates contains a PEST site (a calpain protease sensitive site) (Espreafico, et al, 1992) and a C-terminal globular region containing an AF-6 homology domain (Ponting, 1995).
Myosin Va is a processive motor protein with a high duty ratio (high proportion of its ATPase cycle spent attached to its actin filament track) and a large step size (up to 36nm compared with 5nm for myosin II) (De La Cruz et al, 1999; Mehta et al, 1999; Walker et al, 2000). These properties make it ideally suited for its role in membrane trafficking, polarised cell growth and specific transport pathways.
Most of our information on the functions of myosin V have been gained by analysing mutants in mouse and yeast. In the dilute mouse functional myosin V is absent (Mercer et al, 1991) and the resulting loss of coat colour and neurological disorders are due to defects in melanosome transport in melanocytes and smooth ER trafficking in neurons (Wu et al, 1997; Tabb et al, 1998). Available data support a model where melanosomes are transported from the cell body to the melanocyte dendrites by microtubule based motors and their subsequent movement and tethering at the cell periphery is dependent on myosin V and actin (Wu et al, 2000). Further support for such a model has been provided by colocalisation and binding studies which have shown direct interaction of the myosin V tail with kinesin tail (Huang et al, 1999). Close cooperation between the kinesin/microtubule and myosinV/actin systems is also evident in work on melanophore transport in frog and fish (Rodionov et al, 1998). Absence of myosin V maybe the cause of a dilute phenotype in humans, known as Griscelli syndrome (Pastural, et al, 1997).
In yeast, the class V myosin (myo4p) is required for the transport of maternal mRNA (ASH1) to the daughter cell to maintain mating type (Arn & Macdonald, 1998) whereas the other myosin V, myo2p, is involved in vacuolar inheritance and vesicle trafficking in exocytosis (Brown, 1997). Mutations in myo2p lead to defects in secretion suggesting that this myosin maybe responsible for moving secretory vesicles along actin filaments to polarised regions of the cell. There is also a suggestion of a relationship between myosin V and kinesin in yeast where the temperature sensitive mutant (Myo2p66) can be suppressed by the kinesin-like protein SMY1 (Brown, 1997).
Although the myosin V mutants in mouse and yeast have provided a wealth of information on the multiple functions of myosin V (especially its roles in organelle transport) it is still not known with certainty whether the loss of function observed in these mutants is a direct or indirect consequence of myosin V absence (Reck-Peterson et al, 2000; Wu et al, 2000).
Myosin VI, VII and XV and deafness
These three classes of myosins are associated with genetic deafness disorders in mammals (Hasson, 1997; Redowicz, 1999). Mutations in these myosins result in abnormalities in the stereocilia in the sensory cells of the inner ear of mice; e.g. loss of myosin VI ( Snell's waltzer) leads to fusion of stereocilia whereas when myosin VII is missing (shaker 1) the stereocilia are disorganised and without myosin XV (shaker 2) the stereocilia are very short.
Myosin VI
Myosin VI was first identified
in Drosophila and subsequently in most animal tissues except
in Dictyostelium and yeast (Millar, 1999). Myosin VI is
a 140 kDa molecule that dimerises with a single IQ motif in the
neck and a tail region with a coiled coil domain followed by a
unique globular domain (Kellerman & Millar, 1992). Close to
the converter region between motor domain and neck region there
is an unique insertion, called the "reverse gear", which
enables myosin VI to move towards the pointed or minus end of
actin filaments (in the opposite direction to all other myosins)
(Wells et al, 1999). In Drosophila it has been shown
to be important for movement of cytoplasmic particles, for formation
of the pseudocleavage furrow in embryos, for spermatogenesis and
for egg chamber and imaginal disc morphogenesis (Mermal et
al, 1994). Myosin VI's role as a vesicle transporter on actin
filaments maybe linked with microtubules since it was shown in
Drosophila to coimmunoprecipitate with D-CLIP-190, an orthologue
of human CLIP-170 (a known microtubule binding protein) (Lantz
&Millar, 1998). In mammalian cells myosin VI can be phosphorylated
in vitro in the motor domain close to the actin-binding
interface by a PAK kinase, which is activated by Cdc42 and Rac
suggesting a link with intracellular signalling pathways (Buss
et al, 1998). In polarised cells myosin VI is associated
with the apical domain whilst in sensory hair cells of the inner
ear it is localised in the cuticular plate and the pericuticular
necklace (Hasson et al, 1997)
Myosin VII
Myosin VII has been identified
in Drosophila, C.elegans, pig, mouse (two genes
identified VIIA and B) and human (Sellers, 2000). Mutations in
myosin VII leads to loss of hearing in mice (shaker 1) and humans
(Usher Syndrome type1B- a congenital form of deaf / blindness
or DFNB2 and DFNA11 which are non-syndromic forms of deafness)
(Hasson, 1997; Redowicz, 1999). Myosin VII (240 kDa) is predicted
to be a dimeric molecule with 5 IQ motifs and a tail region with
a short stretch of coiled coil followed by two myosin-tail homology
(MyTH4) domains, two talin-binding (FERM) domains and an SH3-domain.
Very little is known about the function of myosin VII. In hair
cells it is localised to the cuticular plate, where it maybe involved
in maintenance of stereocilia integrity and membrane trafficking
(Hasson et al, 1997). In photoreceptor cells in the retina
it is concentrated in the connecting cilia, where it is proposed
to play a role in phagocytosis and the transport of opsin (Liu
et al, 1997).
Myosin XV
Only one member of this
class has so far been discovered. It was identified as the gene
responsible for the recessive, congenital deafness disorder DFNB3
in humans and shaker 2 in mice (Wang et al, 1998;
Probst et al, 1998) Myosin XV is single headed and at 395
kDa is the largest myosin identified so far. It has a large extension
(1200aa) at the N-terminus of the motor domain, two IQ motifs
and a tail with a similar domain structure to that of the tail
of myosin VII (Liang et al, 1999). This myosin is present
exclusively in the cell body and the stereocilia of hair cells
in the inner ear and in the pituitary gland (Liang et al,
1999).
The plant myosins VIII, XI and XIII
In plant cells a unique subset of myosins comprising classes VIII, XI and XIII have been detected (Kendrick-Jones & Reichelt, 1999).
Myosin VIII
A class VIII myosin was
the first plant myosin gene to be identified (Knight & Kendrick-Jones,
1993). Now six other members of this class are known and they
are predicted to be dimeric with heavy chain sizes of about 130kDa.
They contain an unusual 100-190 residue N-terminal extension prior
to their motor domains, 3-4 IQ motifs, a short region (~70
residues) of predicted a-helical coiled coil and a C-terminal
domain (~150 residues) with no apparent homologies or recognisable
motifs. Myosin VIII appears to play a role in forming the post-cytokinetic
cell wall and in the transport to or through the plasmodesmata
(intercellular channels) in developing cress roots (Reichelt,
et al, 1999).
Myosin XI
Eighteen class XI myosins
genes are now known. They have a heavy chain size of ~170-240kDa
and are similar in molecular structure to the class V myosins
with 5 to 6 IQ motifs and tail regions with predicted coiled coil
domains (forming dimeric molecules) and large C-terminal regions
(Kinema & Schiefelbein, 1994; Reichelt & Kendrick-Jones,
2000). Recent evidence indicates that in the green algae, Chara
and also possibly in higher plants, myosin XIs are responsible
for the extremely rapid organelle transport observed in cytoplasmic
streaming (60mm/s, ten times faster than the speed of the fastest
muscle myosin) (Higashi-Fujime et al, 1995; Morimatsu et
al, 2000).
Myosin XIII
The two myosin genes identified in the green alga, Acetabularia
cliffonii, appear to be monomeric and have been placed in
a new class (class XIII) (Kendrick-Jones & Reichelt, 1999).
Nothing is known about their cellular location or function.
Myosin IX (a signalling / motor protein)
Myosin IXs have been identified in rat, human and C. elegans. They exist in two forms (myr5 and myr7 in rat; Reinhard et al, 1995) which are expressed in a wide variety of tissues and cell types and are believed to be involved in intracellular signalling pathways (Bahler, 2000). They are monomeric with a motor domain containing an N-terminal extension and an insert in the actin binding interface, followed by four to six IQ motifs and a tail region that contains a zinc binding motif and a domain with homology to GTPase activating proteins (GAPs) of the Rho family of G-proteins (Reinhard et al, 1995; Post et al, 1998). Myosin IX acts as a negative regulator of Rho suggesting that it may control the Rho signalling pathways involved in cytoskeleton reorganisation and other cellular processes (Bahler, 2000). However the precise cellular functions of the myosin XIs and their exact roles in the Rho signalling pathways have still to be determined.
Myosin X was first identified in frog inner ear and since then in bovine tissue (Solc et al, 1994). It has a predicted size of 237 kDa with three IQ motifs following the motor domain and a tail containing a region of coiled coil, three pleckstrin homology (PH) domains (found in proteins involved in signal transduction), a myTH4 and a talin-like (FERM) domain (found in myosin VII) (Cheney & Baker, 1999). Nothing is known about the functions of this myosin class.
Only one example has been identified so far in C. elegans and it is the least conserved myosin known (Baker & Titus, 1997). It contains a large tail region (200 kDa) with two MyTH4 domains and a short region of coiled coil but it is not known whether it is a dimeric molecule.
Seven examples of class XIV myosins have been identified to date, all in the parasites Toxoplasma gondii and Plasmodium falciparum (malaria parasite) (Heintzelman & Schwartzman, 1997; Hettmann et al, 2000). They are the simplest myosins known containing a motor domain, no classic IQ motif and variable length tails. These parasites exhibit a unique substrate dependent gliding motility essential for host cell invasion that involves the actin cytoskeleton and myosins. However, although the tails of these myosins contain an essential determinant for plasma membrane localisation, it is not known whether they are involved in the invasion process (Hettmann et al, 2000).
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