Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Myosin I (Myo1)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_529

Nomenclature

The nomenclature of myosins I is confusing, although there is general agreement in the naming of myosins I in vertebrates (Gillespie et al. 2001). The names used in vertebrates, however, do not correspond to those used in lower organisms. The following names have been used to refer to class I myosins:

In yeast: Myo3, Myo5

In Acanthamoeba: Myosin IA-C

In Dictyostelium: MyoA-F, K

In Caenorhabditis elegans: Myo1A or HUM-1; HUM-5

In Drosophila: Myo1A (Myo31DF, CG7438); Myo1B (Myo61F, CG9155)

In vertebrates: Myo1a-h; (MyoA-H in humans)
  • Myo1a (Brush border myosin I, 110-kDa-calmodulin complex)

  • Myo1b (myr 1, myosin-Iα, 130-kDa myosin I)

  • Myo1c (myr 2, myosin-Ιβ,110-kDa myosin I)

  • Myo1d (myr 4, myosin-Iγ, 105-kDa myosin I)

  • Myo1e (myr 3, human myosin-1C)

  • Myo1f

  • Myo1g

  • Myo1h

Historical Background

Myosin 1 is the largest of ∼35 different classes of proteins that comprise the myosin superfamily, a collection of actin-associated molecular motor proteins that use the energy from ATP hydrolysis to translocate actin filaments. In the early 1970s Pollard and Korn identified in the soil amoeba, Acanthamoeba, the first myosin I, a relatively short, single polypeptide chain with an actin-activated ATPase activity resembling that of thick filament-forming myosin (II) from skeletal muscle, which was already known. A major difference was that unlike muscle myosin, the Acanthamoeba protein was single-headed and nonfilamentous. Subsequently, the first myosin I in vertebrates, the 110K-calmodulin complex or brush border myosin I (renamed Myo1a), was identified by several different research groups. In vertebrates, Myo1a forms lateral links that connect the core bundle of actin filaments in intestinal microvilli to the microvillar membrane. It is now known that multiple class I myosins are expressed in cells including two class I myosins in yeast (Myo3 and Myo5); three class I myosins in Acanthamoeba (myosin IA-C); 7 class I myosins in the slime mold, Dictyostelium (MyoA-F, K); 2 in the nematode, Caenorhabditis elegans (Myo1A or HUM-1; HUM-5); 2 class I myosins in the fly, Drosophila melanogaster (Myo1A and Myo1B); and 8 class I myosins in humans (Myo1A-H), and that these myosins are involved in a variety of different cellular events. More comprehensive recent reviews with extensive references are available (Coluccio 2008; Kim and Flavell 2008).

Myosin Structure

Myosins I are single polypeptide chains of 110–140 kDa containing a motor domain, a light-chain-binding domain (LCBD), and a tail region.

As with all myosins, the motor domains of class I myosins contain the nucleotide- and actin-binding sites. They share many of the highly conserved amino acid residues found in myosin II and other myosins. So far, the only available atomic structure of a class I myosin is that of the motor domain of Dictyostelium MyoE (Kollmar et al. 2002), which resembles the available solved structures of other myosin motor domains, although the surface loops differ in length and the position of the lever arm is 30° further up.

The LCBD of class I myosins is an alpha-helical region containing one or more repeats of ∼29 amino acids called IQ regions for the isoleucine and glutamine residues that are normally present. The LCBDs of class I myosins bind calmodulin or light chains that resemble calmodulin. Alternate splicing can occur in the LCBD, e.g., mammalian Myo1b has 6 IQ regions, but is alternatively spliced in the cell to 4-IQ and 5-IQ forms. The sequences of the IQ domains vary among isoforms, as does the affinity of the light chains for the specific IQ domain, suggesting that the myosins might not have a full complement of light chains under all intracellular conditions.

Although the C-terminal tails of class I myosins are diverse, they all contain a membrane-binding domain with different affinities for specific phosphoinositides, which might account for differential localization of myosins I in cells (Fig. 1). Unlike short-tailed myosins I which contain only the membrane-binding domain, other class I myosins are long-tailed, which contain in some cases an ATP-insensitive actin-binding site and a Src-homology 3 (SH3) domain common to many proteins involved in signal transduction. In yeast, the SH3 domain binds proline-rich regions in the WASP-like adapter protein, Bee1p/Las17, and the actin-binding protein, verpolin (Vrp1p), which is analogous to human WASP-interacting protein (WIP). Verpolin is important in the localization of the yeast class I myosins, Myo3 and Myo5, to cortical structures found at sites of polarized growth and actin organization. Myo3/Myo5 and Bee1p bind and stimulate the actin-nucleating properties of the Arp2/3 complex (Anderson et al. 1998). The amoeboid myosins I also regulate actin assembly, but through a mechanism different from that of yeast. The SH3 domains of MyoB and MyoC from Dictyostelium bind a linker protein known as CARMIL (an analogous protein, Acan125, is found in Acanthamoeba), which associates with the Arp2/3 complex and capping protein to mediate actin assembly (Jung et al. 2001).
Myosin I (Myo1), Fig. 1

Schematic of short-tailed and long-tailed class I myosins showing the differences in tail domains. In addition to the membrane-binding domain found in short-tailed myosins I, long-tailed class I myosins contain in some cases an ATP-insensitive actin-binding site and an SH3 domain found in signaling proteins

Phylogenetic trees show that class I myosins, which probably resemble the first myosin, are related evolutionarily and can be divided into four subclasses based on the amino acid sequences of their motor domains. The amoeboid myosins I and long-tailed vertebrate Myo1e and Myo1f constitute subclass 1. Vertebrate Myo1a and Myo1b constitute subclass 2. Vertebrate Myo1c and Myo1h constitute subclass 3. Vertebrate Myo1d and Myo1g, along with Drosophila 1A and C. elegans HUM-1 and HUM-5, constitute subclass 4.

Biochemical and Mechanical Properties

Actin activates the Mg2+-ATPase activity of the lower eukaryotic class I myosins 60-fold to a level similar to that of rabbit skeletal muscle myosin II; however, the ATPase activity of vertebrate class I myosins is only modestly activated by actin. Kinetic analyses indicate that class I myosins spend most of their time weakly bound to actin (i.e., they have a low duty ratio). Activation of the steady-state ATPase activity of myosins I can show a hyperbolic relationship with increasing actin concentration (e.g., Myo1a, Myo1b, Myo1c) or be triphasic (e.g., Acanthamoeba IA and IB, vertebrate Myo1e) with activation at low actin concentrations, inhibition at moderate actin concentrations, and further activation at high actin concentrations. This triphasic behavior was originally attributed to the presence of an ATP-insensitive actin-binding site in the tail; however, Myo1e does not have an ATP-insensitive actin-binding site, so the reason for this triphasic behavior remains unclear (see El-Mezgueldi and Bagshaw 2008).

Single-molecule mechanical studies showed that the interaction of myosin I with actin occurs in two parts representing release of inorganic phosphate followed by ADP release (Veigel et al. 1999; Batters et al. 2004). These results together with results from structural studies showing that class I myosins undergo an ADP-induced conformational change and kinetic studies showing that the change in fluorescence when ATP is added to pyrene actin-myosin I is biphasic, consisting of a fast phase followed by a slow phase, led to the hypothesis that some class I myosins are sensitive to strain (Coluccio and Geeves 1999). This hypothesis is supported by other single-molecule studies showing that the rate of detachment of Myo1b from actin decreases 75-fold under tension (Laakso et al. 2008). Furthermore, membrane tension increases in cells overexpressing class I myosins (Nambiar et al. 2009).

Regulation

Phosphorylation of a single serine or threonine between the ATP- and actin-binding sites in the heavy chain of the Acanthamoeba and Dictyostelium myosins I regulates their actin-activated Mg2+-ATPase and motor activities. Phosphorylation by the myosin I heavy chain kinase, MIHCK, which is a p21-activated kinase (PAK) enhances the ATPase activity 40–80 fold (Brzeska et al. 1997). In vertebrate myosins I, negatively charged glutamate or aspartate is present at the corresponding site, known as the TEDS site after the one-letter codes for the amino acids found at the site, indicating that these myosins I are constitutively active (Bement and Mooseker 1995).

The vertebrate class I myosins translocate actin filaments in vitro albeit slowly. Although the ATPase activity is higher in calcium vs. EGTA, the rate of actin translocation is less in buffers containing calcium. This inhibition is reversed in the presence of exogenous calmodulin suggesting that calcium causes calmodulin dissociation from the LCBD thereby compromising its function as a lever arm and ability to support motility. In the case of Myo1c, calmodulin dissociation might reveal sites that are then available to interact with receptors on hair cells in the inner ear (Cyr et al. 2002).

The steady-state ATPase activity of a fragment of mammalian Myo1c consisting of the motor domain and first IQ domain, Myo1c1IQ, is relatively insensitive to calcium; however, individual steps in the cyclic interaction of Myo1c1IQ with actin including the ATP hydrolysis step (7-fold inhibition) and ADP release (10-fold acceleration) are sensitive to calcium, which would result in acceleration in the detachment of the Myo1c crossbridge and lengthening of the lifetime of the detached M-ATP state (Adamek et al. 2008). This modulation by calcium could have important implications, especially for Myo1c function in the inner ear, where mechanotransduction involves changes in free calcium concentration as channels open and close in response to sound and vibration.

Function

Yeast in which one of the two class I myosins, Myo3 and Myo5, is deleted have no phenotype, although cells in which both myosins are deleted round up and exhibit an accumulation of intracellular vesicles and sensitivity to osmotic shock. The three myosin I isoforms from Acanthamoeba – myosin 1A, 1B, and 1C – have both distinct and overlapping localization patterns and functions. Each is associated with the cell membrane, but only myosin 1C is found at contractile vacuoles. Amoebae loaded with anti-myosin 1C, but not anti-myosin 1B, become large with vacuoles and lyse in response to osmotic shock suggesting that myosin 1C is involved in the expulsion of water from contractile vacuoles. Dictyostelium amoebae are viable when any one of the seven myosin I genes expressed in that organism is deleted demonstrating functional redundancy among the isoforms. Amoebae lacking MyoA or MyoB show defects in speed of locomotion, formation of pseudopods, and directionality of movement. Cells, in which two or three isoforms are deleted, are deficient in pseudopod formation, motility, pinocytosis, membrane ruffling, endocytosis, secretion, and cortical tension (Ostap and Pollard 1996).

The two myosin I isoforms in Drosophila, Myo1A and Myo1B, are most closely related to mammalian Myo1d and Myo1c, respectively and are implicated in left-right symmetry (Hozumi et al. 2006; Spéder et al. 2006). Although both isoforms are expressed in brush border of the midgut, Myo1b is found along the length of the apical microvilli and is required for integrity of the brush border and resistance to bacterial infection (Hegan et al. 2007).

Significant progress in understanding the roles of the class I myosins in mammalian cells is being made. Although there are defects in the morphology of the microvillar membrane, mice in which expression of Myo1a is knocked out show little change in phenotype indicating that other myosins substitute for the loss of Myo1a (Benesh et al. 2010). Unlike Myo1a, which is found predominantly in intestine, Myo1b, which is most closely related to Myo1a, is ubiquitously expressed. Overexpression of Myo1b affects the distribution of endocytotic compartments suggesting that Myo1b plays a role in endocytosis (Raposo et al. 1999). Myo1c, also found in a variety of different cell types, supports the insulin-induced exocytic fusion of vesicles containing GLUT4 in adipocytes (Bose et al. 2002). In the specialized hair cells of the inner ear, Myo1c mediates adaptation, a process by which stimulated cells remain sensitive to new stimuli (Holt et al. 2002). In Xenopus eggs Myo1c plays a role in the compensatory endocytosis of cortical granule membranes after secretion (Sokac et al. 2006). Nuclear Myo1c, which differs from Myo1c by the presence of an N-terminal extension, supports RNA synthesis (Hofmann et al. 2006), although the exact mechanism is unknown. Myo1d plays a role in endocytic membrane trafficking (Huber et al. 2000). Mice in which Myo1e, which is associated with podocytes in kidney, is knocked out show signs of kidney disease (Krendel et al. 2009). Myo1f is expressed predominantly in the spleen, lymph, thymus, and lung; and neutrophils from Myo1f knockout mice exhibit decreased motility and increased adhesion making the mice more susceptible to infection (Kim et al. 2006). Knock-down experiments show that Myo1g, which is expressed exclusively in hematopoietic cells, regulates cell elasticity (Olety et al. 2010).

Summary

Myosins I are a diverse group of single-headed, actin- and membrane-associated molecular motors with roles in a variety of cytoskeletal-membrane events.

References

  1. Adamek N, Coluccio LM, Geeves MA. Calcium sensitivity of the cross-bridge cycle of Myo1c, the adaptation motor of the inner ear. Proc Natl Acad Sci U S A. 2008;105:5710–5.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Anderson BL, Boldogh I, Evangelista M, Boone C, Greene LA, Pon LA. The Src homology domain 3 (SH3) of a yeast type I myosin, Myo5p, binds to verprolin and is required for targeting to sites of actin polarization. J Cell Biol. 1998;141(6):1357–70.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Batters C, Arthur CP, Lin A, Porter J, Geeves MA, Milligan RA, et al. Myo1c is designed for the adaptation response in the inner ear. EMBO J. 2004;23:1433–40.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Bement WM, Mooseker MS. TEDS rule: a molecular rationale for differential regulation of myosins by phosphorylation of the heavy chain head. Cell Motil Cytoskeleton. 1995;31(2):87–92.PubMedCrossRefGoogle Scholar
  5. Benesh AE, Nambiar R, McConnell RE, Mao S, Tabb DL, Tyska MJ. Differential localization and dynamics of class I myosins in the enterocyte microvillus. Mol Biol Cell. 2010;21(6):970–8.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Bose A, Guilherme A, Robida SI, Nicoloro SM, Zhou QL, Jiang ZY, et al. Glucose transporter recycling in response to insulin is facilitated by myosin Myo1c. Nature. 2002;420(6917):821–4.PubMedCrossRefGoogle Scholar
  7. Brzeska H, Knaus UG, Wang ZY, Bokoch GM, Korn ED. p21-activated kinase has substrate specificity similar to Acanthamoeba myosin I heavy chain kinase and activates Acanthamoeba myosin I. Proc Natl Acad Sci U S A. 1997;94(4):1092–5.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Coluccio LM. Myosin I. Proteins Cell Reg. 2008;7:95–124.CrossRefGoogle Scholar
  9. Coluccio LM, Geeves MA. Transient kinetic analysis of the 130-kDa myosin I (myr 1 gene product) from rat liver: a myosin I designed for maintenance of tension? J Biol Chem. 1999;274:21575–80.PubMedCrossRefGoogle Scholar
  10. Cyr JL, Dumont RA, Gillespie PG. Myosin-1c interacts with hair-cell receptors through its calmodulin-binding IQ domains. J Neurosci. 2002;22(7):2487–95.PubMedGoogle Scholar
  11. El-Mezgueldi M, Bagshaw CR. The myosin family: biochemical and kientic properties. Proteins Cell Reg. 2008;7:55–93.CrossRefGoogle Scholar
  12. Gillespie PG, Albanesi JP, Bähler M, Bement WM, Berg JS, Burgess DR, et al. Myosin-I nomenclature. J Cell Biol. 2001;155(5):703–4.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Hegan PS, Mermall V, Tilney LG, Mooseker MS. Roles for Drosophila melanogaster myosin 1B in maintenance of enterocyte brush-border structure and resistance to the bacterial pathogen Pseudomonas entomophila. Mol Biol Cell. 2007;18:4625–36.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Hofmann WA, Vargas GM, Ramchandran R, Stojiljkovic L, Goodrich JA, de Lanerolle PA. Nuclear myosin I is necessary for the formation of the first phosphodiester bond during transcription initiation by RNA polymerase II. J Cell Biochem. 2006;99:1001–9.PubMedCrossRefGoogle Scholar
  15. Holt JR, Gillespie SKH, Provance DW, Shah K, Shokat KM, Corey DP, et al. A chemical-genetic strategy implicates myosin-1c in adaptation by hair cells. Cell. 2002;108(3):371–81.PubMedCrossRefGoogle Scholar
  16. Hozumi S, Maeda R, Taniguchi K, Kanai M, Shirakabe S, Sasamura T, et al. An unconventional myosin in Drosophila reverses the default handedness in visceral organs. Nature. 2006;440:798–802.PubMedCrossRefGoogle Scholar
  17. Huber LA, Fialka I, Paiha K, Hunziker W, Sacks DB, Bähler M, et al. Both calmodulin and the unconventional myosin Myr4 regulate membrane trafficking along the recycling pathway of MDCK cells. Traffic. 2000;1:494–503.PubMedCrossRefGoogle Scholar
  18. Jung G, Remmert K, Wu X, Volosky JM, Hammer 3rd JA. The Dictyostelium CARMIL protein links capping protein and the Arp2/3 complex to type I myosins through their SH3 domains. J Cell Biol 2001;153(7):1479–1497.Google Scholar
  19. Kim SV, Flavell RA. Myosin I: from yeast to human. Cell Mol Life Sci. 2008;65:2128–37.PubMedCrossRefGoogle Scholar
  20. Kim SV, Mehal WZ, Dong X, Heinrich V, Pypaert M, Mellman I, et al. Modulation of cell adhesion and motility in the immune system by Myo1f. Science. 2006;314:136–9.PubMedCrossRefGoogle Scholar
  21. Kollmar M, Dürrwang U, Kliche W, Manstein DJ, Kull FJ. Crystal structure of the motor domain of a class-I myosin. EMBO J. 2002;21(11):2517–25.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Krendel M, Kim SV, Willinger T, Wang T, Kashgarian M, Flavell RA, et al. Disruption of Myosin 1e promotes podocyte injury. J Am Soc Nephrol. 2009;20(1):86–94.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Laakso JM, Lewis JH, Shuman H, Ostap EM. Myosin I can act as a molecular force sensor. Science. 2008;321(5885):133–6.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Nambiar R, McConnell RE, Tyska MJ. Control of cell membrane tension by myosin-I. Proc Natl Acad Sci U S A. 2009;106(29):11972–7.PubMedPubMedCentralCrossRefGoogle Scholar
  25. Olety B, Wälte M, Honnert U, Schillers H, Bähler M. Myo1g is a haematopoietic specific myosin that localises to the plasma membrane and regulates cell elasticity. FEBS Lett. 2010;584:493–9.PubMedCrossRefGoogle Scholar
  26. Ostap EM, Pollard TD. Overlapping functions of myosin-I isoforms? [comment]. J Cell Biol. 1996;133(2):221–4.PubMedCrossRefGoogle Scholar
  27. Raposo G, Cordonnier MN, Tenza D, Menichi B, Dürrbach A, Louvard D, et al. Association of myosin I alpha with endosomes and lysosomes in mammalian cells. Mol Biol Cell. 1999;10(5):1477–94.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Sokac AM, Schietroma C, Gundersen CB, Bement WM. Myosin-1c couples assembling actin to membranes to drive compensatory endocytosis. Dev Cell. 2006;11:629–40.PubMedPubMedCentralCrossRefGoogle Scholar
  29. Spéder P, Ádám G, Noselli S. Type 1D unconventional myosin controls left-right asymmetry in Drosophila. Nature. 2006;440:803–7.PubMedCrossRefGoogle Scholar
  30. Veigel C, Coluccio LM, Jontes JD, Sparrow JC, Milligan RA, Molloy JE. The motor protein myosin-I produces its working stroke in two steps [see comments]. Nature. 1999;398(6727):530–3.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Boston Biomedical Research InstituteWatertownUSA