Trends in Cell Biology
Myosin-X: a molecular motor at the cell's fingertips
Introduction
The actin-based motor proteins of the myosin superfamily power many cellular movements. The myosin superfamily can be divided into at least 20 structurally and functionally distinct classes [1]. However, it is sometimes operationally split into the ‘conventional myosins’, which are responsible for processes such as muscle contraction, and the ‘unconventional myosins’, a category that contains all other myosins. Virtually all myosins have a general body plan consisting of a conserved myosin-head domain, which functions as a motor, a neck domain, which binds to light chains of the calmodulin superfamily and often acts as a switch to regulate motor activity, and a specialized tail domain that is responsible for processes such as cargo binding. Although myosins have long been hypothesized to be involved in phagocytosis and the extension of cellular processes, classic deletion experiments in the slime mold Dictyostelium reveal that these processes occur in the absence of conventional myosin (class II) [2], thus focusing attention on the unconventional myosins. One large group of unconventional myosins (classes VII, X, XII and XV) has been recognized recently as sharing a conserved structural feature in their tail domains–the presence of a myosin tail homology 4 (MyTH4) domain followed by a band 4.1, ezrin, radixin, moesin (FERM) domain. This has led to the suggestion that these myosins constitute a ‘superclass’ of structurally related myosins (Figure 1) 1, 3. The initial characterization of MyTH-FERM myosins such as myosin-X (Myo10) indicates that they might be key mediators of membrane–cytoskeleton interactions in processes such as phagocytosis and the extension of filopodia.
Section snippets
Discovery and structure of Myo10
Myo10 was discovered originally in a PCR screen to identify myosins that are expressed in the inner ear [4]. Phylogenetic analysis of the motor domain of Myo10 revealed that it was not closely related to known myosins and is the founding member of a novel class of myosins called the class X myosins. The full-length Myo10 heavy chain is ∼240 kDa and can be divided into a head, neck and tail (Figure 2) 5, 6. As with other myosins, the head functions as a motor domain and can bind to actin
Distribution and biochemical properties of Myo10
Myo10 appears to be vertebrate specific and is not present in either C. elegans or Drosophila. Although Myo10 is expressed in most vertebrate cells and tissues, it appears to be expressed at relatively low levels – on the order of hundreds or perhaps a few thousand copies per cell [5]. A short form of Myo10 is expressed in the brain [5]. Preliminary data indicate that this unusual isoform lacks most of the motor domain and is a nearly ‘headless’ myosin [24]. Interestingly, several proteins that
Localization of myosins to the tips of filopodia
One of the most intriguing features of Myo10 is its localization at the tips of filopodia (Figure 3) 5, 27. Filopodia are slender cellular extensions that contain a core of bundled actin filaments and appear to function as fingers or sensors that explore and interact with a cell's surroundings. Because filopodia and related structures, such as microvilli and stereocilia, grow by polymerization of actin at their tips, there is much interest in the molecular machinery that regulates
Intrafilopodial motility
Live-cell imaging in HeLa cells led to the discovery that GFP-Myo10 is present at the tips of filopodia during both extension and retraction [27]. This indicates that Myo10 either translocates along the actin filaments as quickly as they polymerize or is pushed ahead by the growing actin bundle. Importantly, in substrate-attached filopodia, puncta of GFP-Myo10 occasionally release from the tip and move rearward at 10–20 nm s−1, which is the rate of retrograde actin flow in these filopodia. In
What do myosins do at the tips of filopodia?
The localization of Myo10 at the tips of filopodia and its filopodia-promoting effects raise the question of the role of myosins at the tips of filopodia. As discussed above, the forward intrafilopodial motility of Myo10 indicates that it might deliver materials that are required for filopodial extension. Another possibility is that myosin-generated forces directly facilitate actin polymerization at the tip by pushing the plasma membrane away from the barbed end, thus creating space to allow
Other MyTH-FERM myosins
In addition to Myo10, vertebrates express three other MyTH-FERM myosins: Myo7a, Myo7b and Myo15a [1]. Myo7a is the subject of intensive study because its mutation results in several forms of deafness including Usher Syndrome 1b, which is the most common form of hereditary deaf–blindness in humans [57]. Myo7a localizes along stereocilia (actin-based extensions that are similar to giant microvilli) in hair cells of the inner ear, and appears to have a role in linking the stereociliary plasma
Concluding remarks
Research with the MyTH-FERM myosins raises many questions for future study. What are the native structures of these proteins and the properties of their motor domains? Do MyTH-FERM myosins have key roles in the formation of actin bundles in structures such as filopodia, microvilli and stereocilia? If the filopodial-tip complex is a specialized site of polymerization, signaling and adhesion, what are its components, and how is it related to other adhesive structures such as focal adhesions and
Acknowledgements
AS was supported by NIH grant 1-P60-DE-13079 to the UNC Comprehensive Center for Inflammatory Disease and RC is supported by NIH/NIDCD grant DC03299.
References (75)
Myosin VIIb, a novel unconventional myosin, is a constituent of microvilli in transporting epithelia
Genomics
(2001)Mouse myosin X: molecular architecture and tissue expression as revealed by northern blot and in situ hybridization analyses
Biochem. Biophys. Res. Commun.
(2000)Motor function and regulation of myosin X
J. Biol. Chem.
(2001)- et al.
The tumor-sensitive calmodulin-like protein is a specific light chain of human unconventional myosin x
J. Biol. Chem.
(2001) - et al.
PEST sequences and regulation by proteolysis
Trends Biochem. Sci.
(1996) - et al.
PI 3-kinases and PTEN: how opposites chemoattract
Cell
(2002) The spatial and temporal dynamics of pleckstrin homology domain binding at the plasma membrane measured by imaging single molecules in live mouse myoblasts
J. Biol. Chem.
(2004)Characterization of the human and mouse unconventional myosin XV genes responsible for hereditary deafness DFNB3 and shaker 2
Genomics
(1999)A novel plant calmodulin-binding protein with a kinesin heavy chain motor domain
J. Biol. Chem.
(1996)The FERM domain: a unique module involved in the linkage of cytoplasmic proteins to the membrane
Trends Biochem. Sci.
(1998)
Structure of the ERM protein moesin reveals the FERM domain fold masked by an extended actin binding tail domain
Cell
PTB or not PTB–that is the question
FEBS Lett.
The talin-tail interaction places integrin activation on FERM ground
Trends Biochem. Sci.
MAX-1, a novel PH/MyTH4/FERM domain cytoplasmic protein implicated in netrin-mediated axon repulsion
Neuron
Mechanism of action of myosin X, a membrane-associated molecular motor
J. Biol. Chem.
Cellular motility driven by assembly and disassembly of actin filaments
Cell
MYO1A (Brush Border Myosin I) Dynamics in the Brush Border of LLC-PK1-CL4 Cells
Biophys. J.
Motor domain-dependent localization of myo1b (myr-1)
Curr. Biol.
Myosin X transports Mena/VASP to the tip of filopodia
Biochem. Biophys. Res. Commun.
Antagonism between Ena/VASP proteins and actin filament capping regulates fibroblast motility
Cell
Cytoskeletal dynamics and nerve growth
Neuron
Classification of pediatric acute lymphoblastic leukemia by gene expression profiling
Blood
Comprehensive proteomic analysis of human Par protein complexes reveals an interconnected protein network
J. Biol. Chem.
A role for myosin VII in dynamic cell adhesion
Curr. Biol.
A class VII unconventional myosin is required for phagocytosis
Curr. Biol.
Myosin-X is a high duty ratio motor
J. Biol. Chem.
A millennial myosin census
Mol. Biol. Cell
Disruption of the Dictyostelium myosin heavy chain gene by homologous recombination
Science
Molecular cloning of myosins from the bullfrog saccular macula: a candidate for the hair cell adaptation motor
Aud. Neurosci.
Myosin-X, a novel myosin with pleckstrin homology domains, associates with regions of dynamic actin
J. Cell Sci.
Identification and analysis of PH domain-containing targets of phosphatidylinositol 3-kinase using a novel in vivo assay in yeast
EMBO J.
Imaging myosin 10 in cells
Biochem. Soc. Trans.
The phosphoinositide 3-kinase pathway
Science
A microtubule-binding myosin required for nuclear anchoring and spindle assembly
Nature
Structural basis of the membrane-targeting and unmasking mechanisms of the radixin FERM domain
EMBO J.
Myosin-X provides a motor-based link between integrins and the cytoskeleton
Nat. Cell Biol.
Myosin-X in brain: developmental regulation, identification of a headless isoform, and dynamics in neurons
Mol. Biol. Cell
Cited by (105)
MYH9: A key protein involved in tumor progression and virus-related diseases
2024, Biomedicine and PharmacotherapyLength control of long cell protrusions: Rulers, timers and transport
2022, Physics ReportsSqueezing in a Meal: Myosin Functions in Phagocytosis
2020, Trends in Cell BiologyThe Antiparallel Dimerization of Myosin X Imparts Bundle Selectivity for Processive Motility
2018, Biophysical JournalCompetition between Coiled-Coil Structures and the Impact on Myosin-10 Bundle Selection
2016, Biophysical JournalCitation Excerpt :Myosin-10 transports several cell-surface receptors to filopodial tips in vertebrate cells (1–3).