Impact of Anti-S2 Peptides on a Variety of Muscle Myosin S2 Isoforms and Hypertrophic Cardiomyopathy Mutants Revealed by Fluorescence Resonance Energy Transfer and Gravitational Force Spectroscopy Page: I
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Aboonasrshiraz, Negar. Impact of Anti-S2 Peptides on a Variety of Muscle Myosin S2
Isoforms and Hypertrophic Cardiomyopathy Mutants Revealed by Fluorescence Resonance
Energy Transfer and Gravitational Force Spectroscopy. Doctor of Philosophy (Biochemistry
and Molecular Biology), August 2020, 89 pp., 7 tables, 28 figures, references, 81 titles.
Myosin subfragment-2 (S2) is an intrinsically unstable coiled coil. This dissertation tests
if the mechanical stability of myosin S2 would influence the availability of myosin S1 heads to
actin thin filaments. The elevated instability in myosin S2 coiled coil could be one of the causes
for hypercontractility in Familial Hypertrophic Cardiomyopathy (FHC). As hypothesized FHC
mutations, namely E924K and E930del, in myosin S2 displayed an unstable myosin S2 coiled
coil compared to wild type as measured by Fluorescence Resonant Energy Transfer (FRET) and
gravitational force spectroscopy (GFS). To remedy this, anti-S2 peptides; the stabilizer and the
destabilizer peptides by namesake were designed in our lab to increase and decrease the stability
of myosin S2 coiled coil to influence the actomyosin interaction. Firstly, the effectiveness of
anti-S2 peptides were tested on muscle myosin S2 peptides across MYH11 (smooth), MYH7
(cardiac), and MYH2 (skeletal) with GFS and FRET. The results demonstrated that the
mechanical stability was increased by the stabilizer and decreased by the destabilizer across the
cardiac and skeletal myosin S2 isoform but not for the smooth muscle isoform. The destabilizer
peptide had dissociation binding constants of 9.97 x 10-1 pM to MYH7 isoform, 1.00 pM to
MYH2 isoform, and no impact on MYH11, and the stabilizer peptide had dissociation binding
constants of 2.12 x 10-2 pM to MYH7 isoform, 3.41 x 10-1 pM to MYH2 isoform, and no
impact on MYH11 revealed by FRET. In presence of the stabilizer, FRET assay, affinity of the
E930del and E924K increased by 10.23 and 0.60 fold respectively. The force required to uncoil
muscle myosin S2 peptides in the presence of the stabilizer peptide was more than in its absence
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Aboonasrshiraz, Negar. Impact of Anti-S2 Peptides on a Variety of Muscle Myosin S2 Isoforms and Hypertrophic Cardiomyopathy Mutants Revealed by Fluorescence Resonance Energy Transfer and Gravitational Force Spectroscopy, dissertation, August 2020; Denton, Texas. (https://digital.library.unt.edu/ark:/67531/metadc1707335/m1/2/: accessed July 17, 2024), University of North Texas Libraries, UNT Digital Library, https://digital.library.unt.edu; .