Research Interests: The long-term goal of research in my lab is … Li, R. H., Stern, J. We report a significant decrease in the proportion of myosin heads in the SRX state in homozygous cMyBP-C knockout mice, however heterozygous cMyBP-C knockout mice do not significantly differ from the wild type. While most mutations encode premature stop codons, missense mutations causing single amino acid substitutions are also common. Importantly, C1 but not C0 binds in a position to activate the TF by shifting tropomyosin (Tm) to the "open" structural state. However, TFL was found to be ~0.05μm longer in the right than in the left atrium and Tmod1 expression was increased in the right atrium. 445-50, 2014 Mar. PO Box 245044 McNamara, J. W., Li, A., Smith, N. J., Lal, S., Graham, R. M., Kooiker, K. B., van Dijk, S. J., Remedios, C. G., Harris, S. P., & Cooke, R. (2016). The University of Arizona. Previous studies demonstrated that recombinant proteins containing the motif and flanking regions (e.g., C1C2) affect thin filament movement in motility assays using heavy meromyosin (S1 plus S2) as the molecular motor. 1558-63, 2016 Feb 9. van Dijk, S. J., K. Bezold Kooiker, S. Mazzalupo, Y. Yang, A. S. Kostyukova, D. J. Mustacich, E. R. Hoye, J. Improved left atrial function in the pimobendan group could explain some of the reported survival benefit for HCM cats in CHF. In addition, four missense variants within the tri-helix bundle that are associated with human hypertrophic cardiomyopathy caused either loss-of-function or gain-of-function effects on force. Recombinant proteins that lacked the combination of C1 and the motif did not affect contractile properties. N-Terminal Domains of Cardiac Myosin Binding Protein C Cooperatively Activate the Thin Filament. The myosin-binding protein C motif binds to F-actin in a phosphorylation-sensitive manner. Muscle contraction relies on interaction between myosin-based thick filaments and actin-based thin filaments. Samantha Harris, PhD. The CDA program, established in 2014, provides research training and funding for junior faculty members to foster academic careers in clinical and translational research. PMID: 32483185, Helen Amerongen, PhD was recently awarded a 2020 College of Medicine Mentoring Award, which honors faculty members who demonstrate outstanding commitment to the mentorship of junior faculty. Here we show that N-terminal domains of cMyBP-C containing the MyBP-C "motif," a sequence of approximately 110 amino acids, which is conserved across all MyBP-C isoforms, reduced actin filament velocity under conditions where filaments are maximally activated (i.e. The University of Arizona is an EEO/AA - M/W/D/V Employer. Oldach, M. S., Ueda, Y., Ontiveros, E. S., Fousse, S. L., Harris, S. P., & Stern, J. These results suggest that the C1 domain plus the motif constitute a functional unit of MyBP-C that can activate the thin filament. Co-Chair, Arizona Biological and Biomedical Program. The results provide direct evidence that the N-terminus of cMyBP-C can bind to F-actin in a periodic complex. A mechanism remains elusive partly because the protein can have multiple effects, such as dual biphasic activation and inhibition observed in actin motility assays. Harris, S. P., B. Belknap, R. E. Van Sciver, H. D. White, and V. E. Galkin, "C0 and C1 N-terminal Ig domains of myosin binding protein C exert different effects on thin filament activation. Here we show using cosedimentation binding assays, that the 4 N-terminal domains of murine cMyBP-C (i.e. Effects of cardiac Myosin binding protein-C on actin motility are explained with a drag-activation-competition model. Species-specific differences in the Pro-Ala rich region of cardiac myosin binding protein-C. Shaffer, J. F., Kensler, R. W., & Harris, S. P. (2009). MYK-461 is a recently-described, mechanistically novel small molecule that acts at the sarcomere to specifically inhibit contractility that has been proposed as a treatment for HCM. These results thus contrast with in vitro studies utilizing proteins encoding the human p/a region and C1 domain. (2010). Stern, J. Samantha Harris. Bezold, K. L., Shaffer, J. F., Khosa, J. K., Hoye, E. R., & Harris, S. P. (2013). Harris, S. (2017, February/Spring). Associate Professor Program Affiliations: Cellular and Molecular Medicine; Address: Phone: (520) 621 0291. Annual Marion J Siegman Lectureship Award of American Physiological Society, American Physiological Society, Spring 2019. The C-terminal antibody stripes were slightly displaced axially, demonstrating an axial orientation of the C-terminal three domains, with the C-terminus closer to the M-line. Sarcomeric mutations in cardiac diseases. In vitro studies indicated that the proline-alanine rich (p/a) region and C1 domain are involved in these processes, although effects were greater using human proteins compared to murine proteins (Shaffer et al. Invasive treatment with septal myectomy or alcohol septal ablation can improve symptoms and functional status, but currently available drugs for reducing obstruction have pleiotropic effects and variable therapeutic responses. Recombinant N-terminal proteins also bound to F-actin and inhibited acto-HMM ATPase rates in solution. Pimobendan has been shown to impart a significant survival benefit in cardiomyopathic cats who receive it as part of heart failure therapy. To investigate possible mechanisms by which cMyBP-C limits cross-bridge cycling kinetics we assessed effects of recombinant N-terminal domains of MyBP-C on the ability of heavy meromyosin (HMM) to support movement of actin filaments using in vitro motility assays. The goal of this basic science proposal is to utilize Drosophila melanogaster as a model system to dissect the molecular mechanisms that underlie the assembly, growth, and function of centrioles - the core subunits of centrosomes. In the current study, we have examined L348P, a sequence variant of cMyBP-C first identified in a screen of patients with HCM. To test the hypothesis that changes in ACTC disrupt interactions with cMyBP-C, we examined the interactions between seven ACTC variants and the N-terminal C0C2 fragment of cMyBP-C. We found there was a significant decrease in binding affinity (increase in Kd values) for the A331P and Y166C variants of ACTC. This grant will fund work in the Cusanovich lab aimed at developing better tools for measuring (at single cell resolution) how gene expression and gene regulatory patterns change over time.
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