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Exploring The Effect Of Physiologically Relevant Protein Modifications On Cardiac Muscle Thin Filament Ca2+ Binding And Engineering TnC To Correct Disease Related Aberrant Thin Filament Ca2+ Binding

Liu, Bin
http://rave.ohiolink.edu/etdc/view?acc_num=osu1281981835

Abstract Details

2010, Doctor of Philosophy, Ohio State University, Biophysics.
The Ca2+ sensitivity of cardiac muscle force development can be modulated by physiological or patho-physiological stimuli such as phosphorylation or disease related protein modification. Since troponin C (TnC) is the Ca2+ sensor for cardiac muscle contraction, TnC’s Ca2+ binding properties could be affected by these physiological or patho-physiological related protein modifications. Thus, in this study, we examined the effect of mimicking phosphorylation and disease related protein modifications in TnI and TnT on the Ca2+ binding properties of TnC in a physiologically relevant biochemical model system, i.e. reconstituted thin filaments. Our results demonstrated that these protein modifications alter thin filament Ca2+ binding in a way generally consistent with their effect on myofilament Ca2+ sensitivity. Besides steady state Ca2+ binding affinity, the kinetic rate of Ca2+ dissociation from thin filament was also modulated by these physiologically relevant protein modifications. Generally, the protein modifications that sensitize thin filament Ca2+ binding usually slow the rate of Ca2+ dissociation from thin filament, while those that desensitize thin filament Ca2+ binding usually accelerate the rate of Ca2+ dissociation from thin filament. Experimental evidence suggests that the symptoms of some cardiac dysfunctions may be caused by the aberrant Ca2+ binding. Thus, correcting the aberrant Ca2+ binding might improve cardiac function. To achieve this goal, we have engineered TnC constructs with a wide, yet adjustable, range of Ca2+ binding sensitivities by modulating the negatively charged residues in the Ca2+ chelating loop and/or by replacing key hydrophobic amino acids in the regulatory domain of TnC with polar Gln. We were able to correct both the increased and decreased thin filament Ca2+ sensitivities caused by the disease associated proteins via replacing the wild type TnC with specifically engineered TnC constructs. Additionally, engineered TnC constructs can correct the disease related abnormal Ca2+ sensitivity of the thin filament acto-myosin ATPase assay and the force-pCa relationship in skinned trabeculae isolated from rat hearts. This study can potentially lead to a novel therapeutic strategy for treating cardiac muscle diseases.
Jonathan Davis (Advisor)
Jack Rall (Committee Member)
Peter Reiser (Committee Member)
Paul Janssen (Committee Member)
Troponin Ca2+ cardiac muscle

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Citations

  • Liu, B. (2010). Exploring The Effect Of Physiologically Relevant Protein Modifications On Cardiac Muscle Thin Filament Ca2+ Binding And Engineering TnC To Correct Disease Related Aberrant Thin Filament Ca2+ Binding [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1281981835

    APA Style (7th edition)

  • Liu, Bin. Exploring The Effect Of Physiologically Relevant Protein Modifications On Cardiac Muscle Thin Filament Ca2+ Binding And Engineering TnC To Correct Disease Related Aberrant Thin Filament Ca2+ Binding. 2010. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1281981835.

    MLA Style (8th edition)

  • Liu, Bin. "Exploring The Effect Of Physiologically Relevant Protein Modifications On Cardiac Muscle Thin Filament Ca2+ Binding And Engineering TnC To Correct Disease Related Aberrant Thin Filament Ca2+ Binding." Doctoral dissertation, Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1281981835

    Chicago Manual of Style (17th edition)

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This open access ETD is published by The Ohio State University and OhioLINK.