Lynne M. Coluccio, Ph.D.

Lynne M. Coluccio, Ph.D.

Associate Professor

B.S., State University of New York at Albany
M.S., Rensselaer Polytechnic Institute
Ph.D., Rensselaer Polytechnic Institute

Phone: (617) 638-4002
Fax: (617) 638-4041
E-mail: coluccio@bu.edu
Address: see below
Link to BU Faculty Profile


Research

Role of the class I myosin Myo1c in hearing

Myosins are molecular motor proteins that use the energy from ATP hydrolysis to translocate actin filaments. In general, myosins contain three domains known as the head (motor domain), neck (light chain-binding region) and tail (cargo-binding region). Dozens of different myosins have been identified. They share sequence similarity in the motor domain, which contains the ATP- and actin-binding sites, although they differ in their kinetic interaction with actin. The length of the light-chain binding region and the particular light chain they bind varies among myosins as well as the identity of their binding partners, which can be various cargo, regulatory molecules and/or lipids that associate with the tail domain.

LC-1

Schematic of Myo1c showing functional domains and binding sites for ATP, actin, calmodulin and membrane

The most diverse members of the myosin superfamily are class I myosins, which are single-headed. Eight class I myosins, a-e, are expressed in mammalian cells. Their neck region contains 3-6 so-called IQ domains, which bind calmodulin as the light chain. Class I myosins interact slowly with actin in a Ca2+-regulated manner. The first myosin I to be identified in mammalian cells was Myo1a, which forms the lateral links in intestinal microvilli observed between the core bindle of actin filaments and the membrane. The class I myosin Myo1c, which binds three molecules of calmodulin and associates with lipids through its tail region, has been shown by the Czech group to mediate GLUT4 trafficking in adipocytes.

LC-2

Model of mechano-transduction complex. Modified from Grati and Kachar, 2011.

Our present work focuses on the role of Myo1c in the inner ear, where studies done by Peter Gillespie and his colleagues indicate that it mediates adaptation. Actin-filled projections or stereocilia found in bundles on the hair cells in the cochlea and vestibular organs of the inner ear deflect in response to minute mechanical changes causing increased tension on the extracellular tip links that connect the tips of stereocilia to the sides of the adjacent taller stereocilia. In a generally accepted model of mechanotransduction in both vestibular and cochlear hair cells, transduction channels are attached to an adaptation-motor complex, which controls tip-link tension. Ca2+ entering the transduction channel is thought to bind and regulate the Ca2+-sensitive adaptation motor. During an excitatory stimulus, tension is initially high, causing the channels to open. The motor complex then slips down the actin cytoskeleton, reducing tip-link tension and allowing the channels to close. During a negative stimulus, tension is initially low and the channels close. The motor complex then ascends the actin cytoskeleton, restoring the resting tension and reopening the channels in a process known as slow adaptation. Adaptation, which also contains a fast component due to either a direct effect of Ca2+ on the closure of the transduction channels and/or the release of a mechanical element in series with the transduction apparatus, permits hair cells under prolonged stimuli to remain sensitive to new stimuli. Its location at the upper tip-link density and the spatiotemporal expression of its mRNA in auditory hair cells, which precedes the onset of transduction, and studies showing that slow and fast adaptation are blocked in utricular hair cells from a transgenic mouse expressing a mutant Myo1c that can be selectively inhibited suggest Myo1c as the adaptation motor. Our biochemical, biophysical and structural studies showing that Myo1c contains a strain-sensitive ADP-release mechanism that enables it to bear large loads without detaching from actin are consistent with this role.

We recently studied three mutations in Myo1c that had been found by Zadro and colleagues in patients with hearing defects. Our studies showed that these mutations, which reside in the motor domain, affect the interaction of Myo1c with nucleotide and actin. In one case the mutation resulted in uncoupling of the ATPase activity from the ability of Myo1c to move actin filaments in in vitro motility assays. The studies led us to propose that both climbing adaptation in patients with this particular mutation would be compromised.

Our new studies indicate that Myo1c plays a role in cell-cell contact in polarized epithelial cells. We have determined that cells in which Myo1c expression is reduced by RNAi, lose their polarized shape and become flattened; this effect is reversed by expression of RNAi-resistant Myo1c. Ongoing studies are examining the specific mechanism of action.


Selected Publications

Articles:

Brady, R. J., R. H. Parsons, and L. M. Coluccio. 1981. Nocodazole inhibition of the vasopressin-induced water permeability increase of toad urinary bladder. Biochim. Biophys. Acta 646:399-401.

Koretz, J. F., L. M. Coluccio, and A. M. Bertasso. 1982. The aggregation characteristics of column-purified rabbit skeletal myosin in the presence and absence of C-protein at pH 7.0. Biophy. J. 37:433-440.

Coluccio, L. M., R. J. Brady, and R. H. Parsons. 1983. Pressure effects on the ADH-induced initiation of water flow in toad bladder. Amer. J. Physiol. (Renal, Fluid and Electrolyte Physiol.) F547-553.

Tilney, L. G., E. M. Bonder, L. M. Coluccio, and M. S. Mooseker. 1983. Actin from Thyone sperm assembles on only one end of an actin filament: a behavior regulated by profilin. J. Cell Biol. 97:112-124.

Coluccio, L. M., and L. G. Tilney. 1983. Under physiological conditions actin disassembles slowly from the nonpreferred end of an actin filament. J. Cell Biol. 97:1629-1634.

Coluccio, L. M., and L. G. Tilney. 1984. Phalloidin enhances actin assembly by preventing monomer dissociation. J. Cell Biol. 99:529-535.

Bryan, J., and L. M. Coluccio. 1985. Platelet gelsolin caps and severs actin filaments: a kinetic analysis of depolymerization. J. Cell Biol. 101:1236-1244.

Coluccio, L. M., P. Sedlar, and J. Bryan. 1986. A 45,000-mol-wt protein from unfertilized sea urchin eggs and its 1:1 actin complex differ in their action on actin filaments. J. Muscl. Res. & Cell Motil. 7:133-141.

Coluccio, L. M., and A. Bretscher. 1987. Calcium-regulated cooperative binding of the microvillar 110K-calmodulin complex to F-actin: Formation of decorated filaments. J. Cell Biol. 105: 325-334.

Krizek, J., L. M. Coluccio, and A. Bretscher. 1987. The ATPase activity of the microvillar 110K-calmodulin complex is activated by F-actin in Mg2+ and inhibited in K+-EDTA. FEBS 225:269-272.

Coluccio, L. M., and A. Bretscher. 1988. Mapping the microvillar 110K-calmodulin complex: Calmodulin-associated or -free fragments of the 110 kd polypeptide bind F-actin and retain ATPase activity. J. Cell Biol. 106:367-374.

Bullitt, E., D. DeRosier, L. M. Coluccio, and L. G. Tilney. 1988. Three-dimensional reconstruction of an actin bundle. J. Cell Biol. 107:597-611.

Coluccio, L. M., and A. Bretscher. 1989. Reassociation of microvillar core proteins: Making a microvillar core in vitro. J. Cell Biol. 108:495-502.

Coluccio, L. M., and A. Bretscher. 1990. Mapping of the microvillar 110K-calmodulin complex (brush border myosin 1). Identification of fragments containing the catalytic and F-actin-binding sites and demonstration of a calcium ion dependent conformational change. Biochemistry 29:11089-11094.

Coluccio, L. M. 1991. Identification of the microvillar 110-kDa calmodulin complex (myosin-1) in kidney. E. J. Cell Biol. 56:286-294.

Coluccio, L. M., and C. Conaty. 1993. Myosin-I in mammalian liver. Cell Motil. & Cytoskel. 24:189-199.

Williams, R., and L. M. Coluccio. 1994. Novel 130-kDa rat liver myosin-I will translocate actin filaments. Cell Motil. & Cytoskel. 27:41-48

Coluccio, L. M. 1994. Differential calmodulin binding to three myosin-I isoforms from liver. J. Cell Sci. 107:2279-2284.

Coluccio, L. M. 1994. An end in sight: Tropomodulin. (Invited mini-review) J. Cell Biol. 127:1497-1499.

Balish, M., and L. M. Coluccio. 1995. Identification of brush border myosin-I in liver and testis. Biomed. Biophys. Res. Commun. 211:331-339.

Williams, R., and L. M. Coluccio. 1995. Phosphorylation of myosin-I from rat liver by protein kinase C reduces calmodulin binding. Biochem. Biophys. Res. Commun. 216:90-102.

Coluccio, L. M. 1997. Myosin-I. (Invited review) Amer. J. Physiol. 273:C347-C359.

Veigel, C., L. M. Coluccio, J. D. Jontes, J. C. Sparrow, R. A. Milligan, and J. E. Molloy. 1999. Myosin-I produces its working stroke in two steps. Nature 398:530-533.

Coluccio, L. M., and M. A. Geeves. 1999. 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. 274:21575-21580.

Balish, M. F., E. F. Moeller, III, and L. M. Coluccio. 1999. Overlapping distribution of the 130- and 110-kDa myosin I isoforms on rat liver membranes. Arch. Biochem. Biophys. 370:285-293.

Geeves, M. A., and L. M. Coluccio. 1999. The XXVII European Muscle Conference. (Invited conference report). J. Muscle Research and Cell Motility. 20:807-809.

Li, W., J. W. Wang, L. M. Coluccio, P. Matsudaira and R. J. Grand. 2000. Brush border myosin I: A basally localized transcript in human jejunal enterocytes. J. Histochemistry & Cytochemistry 48:89-94.

Perreault-Micale, C., A. Shushan and L. M. Coluccio. 2000. Truncation of a mammalian myosin I results in loss of Ca2+-sensitive motility. J. Biol. Chem. 275:21624-21630.

Geeves, M. A., C. Perreault-Micale, and L. M. Coluccio. 2000. Kinetic analyses of a truncated mammalian myosin I suggest a novel isomerization event preceding nucleotide binding. J. Biol. Chem. 274:21575-21580.

Wallace, M. I., C. Batters, L. M. Coluccio and J. E. Molloy. 2003. Nanometre resolution tracking of myosin-1b motility. IEE Proc. Nanobiotechnol. 150:134-140.

Batters, C., C. P. Arthur, A. Lin, J. Porter, M. A. Geeves, R. A. Milligan, J. E. Molloy, and L. M. Coluccio. 2004. Myo1c is designed for the adaptation response in the inner ear. EMBO J. 23:1433-1440.

Batters, C., M. I. Wallace, L. M. Coluccio, and J. E. Molloy. 2004b. A model of stereocilia adaptation based on single molecule mechanical studies of myosin-I. Phil. Trans. R. Soc. B. 359:1895-1905.

Stafford, W. S., M. Walker, J. Trinick and L. M. Coluccio. 2005. Mammalian class I myosin, Myo1b, is monomeric and crosslinks actin filaments as determined by hydrodynamic studies and electron microscopy. Biophys. J. 88:384-391.

Clark, R., M. Ansari, S. Dash, M. A. Geeves, and L. M. Coluccio. 2005. Loop 1 of transducer region in Myo1b modulates actin affinity, ATPase activity, and nucleotide access. J. Biol. Chem. 280:30335-30942.

Coluccio, L. M. 2006. Myo1b. AfCS-Nature Molecule Pages. (doi:10.1038/mp.a001573.01). On line at http://www.signaling-gateway.org/molecule/query?afcsid=A001573

Lieto-Trivedi, A., S. Dash and L. M. Coluccio. 2007. Myosin surface loop 4 modulates inhibition of acto-myosin 1B ATPase activity by tropomyosin. Biochemistry 46:2779-2786. PMID: 17298083

Coluccio, L. M. 2008. Myosins: A superfamily of molecular motors, Editor. Vol. 7, Proteins and cell regulation series, Springer Verlag, The Netherlands.

Adamek, N., L. M. Coluccio and M. A. Geeves. 2008. Calcium-sensitive ATP hydrolysis of Myo1c, the adaptation motor in the inner ear. Proc. Natl. Acad. Sci. (USA). 105: 5710-5715. PMID: 18391215 PMCID: PMC2299219

Lieto-Trivedi, A. and L. M. Coluccio. 2008. Calcium, nucleotide and actin affect the interaction of mammalian Myo1c with its light chain calmodulin. Biochemistry 47:10218-10226. PMID: 18729383

Adamek, N., A. Lieto-Trivedi, S. Dash, M. A. Geeves and L. M. Coluccio. 2010. Modification of loop 1 affects the nucleotide-binding properties of Myo1c, the adaptation motor in the inner ear. Biochemistry 49(5):958-71. PMID: 20039646

Wang, C.-L., A. and L. M. Coluccio. 2010. New insights into regulation of the actin cytoskeleton by tropomyosins. Int. Rev. Cell Molec. Biol. 281:91-128. Invited review. PMID:20460184

Komaba, S. and L. M. Coluccio. 2010. Localization of myosin 1b to actin protrusions requires phosphoinositide binding. J. Biol. Chem. 285:27686-27693. PMID: 20610386; PMCID: PMC2934636 [Available on 2011/9/3].

Adamek, N., M. A. Geeves and L. M. Coluccio. 2011. Myo1c mutations associated with hearing loss cause defects in the interaction with nucleotide and actin. Cell. Mol. Life Sci. 68:139-150 PMID: 20039646; PMCID: PMC2826812.

Chinthalapudi, K., M. H. Taft, R. Martin, F. K. Hartmann, S. M. Heissler, G. Tsiavaliaris, H. O. Gutzeit, H-J. Knölker, R. Fedorov, L. M. Coluccio and D. J. Manstein. 2011. Molecular mechanism of pentachloropseudilin-mediated inhibition of myosin motor activity. J. Biol. Chem. 286(34):29700-8. PMID: 21680745; PMCID-in process

Coluccio, L. M. 2013. Myosin I. Encyclopedia of Signaling Molecules. XLVIII. Springer. S. Choi (Ed.) Invited contribution.

Coluccio, L. M. 2013. Myosin. Encyclopedia of Signaling Molecules. XLVIII. Springer. S. Choi (Ed.) Invited contribution.

Tokuo, H. and L. M. Coluccio. 2013. Myo1c mediates E-cadherin-based cell-cell contact in epithelial cells. In revision for Mol. Biol. Cell.

Books:

Coluccio, L. M. 2008. Myosin I. In Myosins: A superfamily of molecular motors, L. M. Coluccio, editor, Vol. 7, Proteins and cell regulation series, pp 95-124, Springer Verlag, The Netherlands.

Contact Us

Department of Physiology and Biophysics
Boston University School of Medicine
700 Albany Street. W410
Boston MA 02118-2518

Phone: (617) 638-4002
Fax: (617) 638-4041
e-mail: coluccio@bu.edu

Directory|BUMC
February 21, 2014
Primary teaching affiliate
of BU School of Medicine