02/12/2025
By Irma Silva
Candidate: Meaghan Barry
Date: Thursday, February 27
Time: 2 – 4 p.m.
Location: Olsen Hall, Room 503
Committee Chair:
Jeffrey Moore (Advisor), Professor, Biological Sciences, University of Massachusetts Lowell
Committee Members:
Matthew Gage, Professor, Chemistry Department, University of Massachusetts Lowell
Nicolai Konow, Associate Professor, Biological Sciences, University of Massachusetts Lowell
William Schmidt, Scientist, ALPCO
Title: Tropomyosin and Troponin I: The Crosstalk of Cardiac Relaxation and Cardiomyopathy
Brief Abstract:
Cardiomyopathies, broadly categorized as hypo- or hyper-contractile, vary in severity based on underlying biophysical disruptions. 35% of genetic cardiomyopathies are due to mutations in the cardiac thin filament. Composed of actin, tropomyosin (Tpm), and troponin (Tn), the thin filament is a part of the regulatory mechanism of muscle contraction. Each heart muscle contraction is driven by translating cytoplasmic calcium concentrations to the three structural and kinetic states of the thin filament. This structural modulation causes the activation and relaxation cycles of each heartbeat. Recent cryo-electron microscopy (cryoEM) provide important insights on vital details of structural changes of the thin filament during regulatory transitions; however, many of these regions remain unresolved particularly at the interface between Tpm and Tn.
This dissertation focuses on translating recent structural insights to the biochemical and function effects of thin filament regulation. I investigated (1) the mechanism of thin filament relaxation through a vital Tpm-TnI interaction, (2) Tpm’s role in TnI phosphorylation-induced lusitropy during sympathetic stimulation, and (3) a hydrophobic pocket at the Tpm overlap region as a target for potential therapeutic intervention in cases of cardiomyopathy. Further, through this body of work, I propose a novel mechanism by which TnI modulates the mechanical properties of Tpm, including its flexibility and curvature and, therefore, sheds light on how minor molecular changes can lead to severe cases of cardiomyopathy.