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Fred
Schachat, Ph.D.
(Biochemistry,
Stanford University)
Associate Professor,
Department of Cell Biology
Programs: CMB, Cancer Center, and Genetics, Physiology
and Cell Biophysics Division
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We
are working in three areas. The first focuses on the mechanisms
that coordinate contractile protein expression in striated
muscle. A variety of approaches, including comparative
genomics, cDNA analysis, PCR, and genetic/biochemical
analyses of expression in transgenic mice and C. elegans
mutants are being used to define the how the expression
of different thin filament proteins is coordinated and
how the accumulation of thick and thin filament proteins
is regulated. As models, we study the troponin-tropomyosin
thin filament calcium regulatory complex of mammalian
skeletal muscle and uncoordinated mutants of the nematode
C. elegans whose phenotypes are consistent with disproportionate
synthesis of thick and thin filament proteins.
The second concerns the biomoleuclar
interactions involved in the cooperative activation of
thin filaments in skeletal muscle contraction. These studies
involve the analysis of Ca2+ and rigor crossbridge activation
of skeletal muscle fibers in the presence of inhibitory
peptides and following the substitution of calmodulin[troponin
C] chimeras for troponin C, the Ca2+-binding subunit of
the thin filament regulatory complex.
The third centers on the novel proteins
and physiological systems responsible for the superfast
contractile properties of extraocular muscle. These include
extraocular myosin, whose gene we have cloned and mapped,
a rare alternative splice variant of troponin T, and selective
amplification of the Ca2+-reuptake system.
Overall, we have characterized the troponin
T (TnT) and tropomyosin (Tm) species expressed in fast
skeletal muscles and identified three programs of TnT-Tm
expression in adult and neonatal muscle. Complementing
physiological studies show that these different TnT-Tm
programs control a muscle fiber's responsiveness to calcium.
Strong evidence that posttranscriptional controls are
critical to the coordinate expression of myofibrillar
proteins has been found; and phylogenetic footprinting
provides evidence for hierarchical control of the extraocular
muscle specific myosin. |
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E-mail
f.schachat@cellbio.duke.edu
354 Sands Bldg, Box 3011
Duke University Medical Center
Durham, NC 27710
Telephone
919-684-6489
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Selected
Publications
McCormick, K. M., Baldwin, K. M. and Schachat, F. (1994)
Coordinate changes in C protein and myosin expression
during skeletal muscle hypertrophy. Am. J. Physiol. 267:
C443-C449.
Briggs, M. M. and Schachat, F. (1996) The physiologically
regulated alternative splicing patterns of fast troponin
T RNA are conserved in mammals. Amer. J. Physiol. 270,
C298-C305.
Abstracts
Schachat, F. and Brandt, P.W. (1999). The troponin I-inhibitory
peptide does not reduce the cooperativity of either calciun
or rigor crossbridge activation. Biophys. J., in press.
Briggs, M. M. and Schachat, F. (1999). Full-Length cDNA
Sequence, Predicted Exon Structure, and Phylogenetic Analysis
of the Novel Myosin in Extraocular and Laryngeal Muscles.
Molec. Biol. Cell, in press.
Blank, J. and Schachat, F. (1999) Extraocular and laryngeal
muscles exhibit differential amplification of proteins
involved in calcium homeostasis. Molec. Biol. Cell, in
press.
Reviews
Schachat, F. and Briggs, M. M. (1990) Expression of fast
thin filament proteins. Defining fiber archetypes in a
molecular continuum. The Dynamic State of Muscle, W. DeGruyter,
Berlin, pp. 279-291.
Reedy, M. K., Reedy, M. M. and Schachat, F. (1994) Tropomyosin:
does resolution lead to reconciliation? Current Biology
4: 624-626. |
Current
Projects
Margaret Briggs (research associate): Troponin T alternative
splicing and thin filament assembly.
Fred Schachat and Margaret Briggs: Regulation of contractile
protein synthesis and assembly in extraocular muscle
Fred Schachat (principal investigator), Sam George (collaborator),
and Phil Brandt (collaborator): Physiological studies
on troponin C[calmodulin] chimeras.
Mary Reedy (collaborator) and Fred Schachat: Myofilament
lattice assembly in C. elegans mutants. |
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