My laboratory primarily studies the structure and cellular function of
the dystrophin-glycoprotein complex, which spans the muscle cell plasma
membrane (or sarcolemma) and links the cortical actin cytoskeleton with
the extracellular matrix. Greater understanding of the physiologic role
of the dystrophin-glycoprotein complex is necessary to understand how its absence
or abnormality leads to several muscular dystrophies and some forms of human
dilated cardiomyopathy. The lab has defined the complete actin-binding
region of 400 kDa dystrophin and shown that its homologue utrophin binds actin
filaments through a distinct molecular mechanism. Novel methods to 
visualize
the sarcolemmal cytoskeleton without interference from internal structures provided
the first evidence that dystrophin functions in vivo to mechanically
stabilize γ-actin filaments in costameres. Studies of dystrophin-deficient
mice and new animal models generated by the lab have provided insight into the
function of costameres in striated muscle and suggest novel links between dystrophin
deficiency and alterations cell signaling, or gene expression manifest by dystrophic
muscle. My lab's unique capability to express biochemical amounts of full-length
dystrophin and utrophin has made possible new studies to i) characterize the
effects of dystrophy-causing point mutations on dystrophin structure/function,
ii) to identify novel associated proteins and iii) to develop new protein-based
therapies for dystrophinopathies.
In a completely new line of investigation, my group is working to determine
the potentially unique roles of non-muscle actin isoforms in the establishment/maintenance
of cell polarity in a variety of tissues. The β- and γ-isoforms
of actin distribute to distinct locations within a variety of polarized cell
types, including neurons, epithelial cells, and hair cells of the inner ear
yet β- and γ-actin differ from each other by only 4 amino acids. Using
new isoform-specific reagents and conditional knock-out mouse lines developed
during the course of our muscular dystrophy studies, the lab is now poised
to identify non-overlapping functions of these two highly conserved and widely
expressed proteins.
Rybakova, I.N., Patel, J.R. and Ervasti, J.M. (2000) The dystrophin complex
forms a mechanically strong link between the sarcolemma and costameric actin. J.
Cell Biol . 150:1209-1214.
Rybakova, I.N., Patel, J.R., Yurchenco, P.D., Davies, K.E.
and Ervasti, J.M. (2002) Utrophin binds laterally along actin filaments and
can couple costameric actin with sarcolemma when overexpressed in dystrophin-deficient
muscle. Mol. Biol. Cell 13:1512-1521 (Published online February
28, 2002, DOI 10.1091/mbc01-09-0446).
Warner, L.E., Dello Russo, C., Crawford, R.W., Rybakova, I.N.,
Patel, J.R., Ervasti, J.M. and Chamberlain, J.S. (2002) Expression of Dp260
in muscle tethers the actin cytoskeleton to the dystrophin-glycoprotein complex
and partially prevents dystrophy. Hum. Mol. Genet. 11:1095-1105.
Galkin, V.E., Orlova, A., VanLoock, M.S., Rybakova, I.N., Ervasti,
J.M. and Egelman, E.H. (2002) The utrophin actin-binding domain binds F-actin
in two different modes: implications for the spectrin superfamily of proteins J.
Cell Biol. 157:243-251.
Ervasti, J.M. (2003) Costameres: the Achilles' Heel of Herculean Muscle. J.
Biol. Chem. 278:13591-13594 (Published online January 29, 2003, DOI
10.1074/jbc.R200021200).
Rybakova, I.N. and Ervasti, J.M. (2005) Identification of spectrin-like
repeats required for high affinity utrophin/actin interaction. J.
Biol. Chem. 280:23018-23023 (Published online April 11, 2005, DOI 10.1074/jbc.M502530200).
Rybakova, I.N., Humston, J.L., Sonnemann, K.J. and Ervasti,
J.M. (2006) Dystrophin and utrophin bind actin filaments through distinct
modes of contact. J. Biol. Chem. 281:9996-10001 (Published online
13 February 2006, 10.1074/jbc.M513121200).
Hanft, L.M., Rybakova, I.N., Patel, J.R., Rafael, J.A. and
Ervasti, J.M. (2006) Cytoplasmic γ-actin contributes to a compensatory
remodeling response in dystrophin-deficient muscle. Proc. National Acad.
Sci. USA 103:5385-5390 (Published online March 24, 2006 10.1073/pnas.0600980103).
Sonnemann, K.J., Fitzsimons, D.P., Patel, J.R., Liu, Y.W., Schneider, M.F.,
Moss, R.L. and Ervasti, J.M. (2006) Cytoplasmic γ-actin is not required
for skeletal muscle development but its absence leads to a progressive myopathy. Dev.
Cell 11:387-397 (Published online September 5, 2006, DOI10.1016/j.devcel.2006.07.001).
Ervasti, J.M. (2006) Dystrophin, its interactions with other proteins,
and implications for muscular dystrophy. BBA Molec. Basis Dis. (In
Press).
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