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The role of myopalladin in muscle function and disease
Kadarla, Vinay K.
Kadarla, Vinay K.
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2020-05
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Dissertation
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Abstract
Decades of research have provided fundamental insight into the human heart’s structure
and function. Yet, most cardiac malformations remain a mystery as scientists and clinicians
continue to examine how inherited mutations and aging affect the normal biological functions of
proteins associated with cardiac dysfunction. Recently, mutations in the muscle protein
myopalladin have been linked to the pathogenesis of cardiomyopathy. Myopalladin is a sarcomeric
protein that is thought to have an important role in maintaining sarcomere structure, signaling and
regulation of gene expression in response to muscle stress. Myopalladin and palladin belong to a
family of closely related immunoglobulin (Ig)-domain containing proteins that have essential, but
unclear roles in organizing the actin cytoskeleton. Recent work in the Beck lab has shown that the
C-terminal Ig domains of palladin bind directly to F-actin and increase both the rate of actin
polymerization and the stability of actin filaments. The fact that a number of mutations in
myopalladin are located within the analogous actin-binding region suggests that a disruption in
actin regulation may occur in cardiomyopathy. Thus, we hypothesized that myopalladin also binds
directly to actin and regulate both the rate of actin polymerization and the stability of actin
filaments. To study the capability of myopalladin to bind and crosslink actin filaments, cosedimentation
assays were performed between purified F-actin and myopalladin Ig domains at
various concentrations. The results suggest that Ig3 domain of myopalladin is the minimal domain
required for both the binding and bundling of F-actin. Pyrene fluorescence was used to monitor
the polymerization rate of G-actin in the presence of various Ig domain of myopalladin. Our data
reveals that myopalladin inhibits the rate of actin polymerization but strongly prevents actin
depolymerization. From our data, we propose that myopalladin is involved in sarcomere structure
and function through regulation of actin dynamics. Also, we suggest that myopalladin may act
both as a scaffold, binding directly to actin and other actin binding proteins at the Z-disc, and by
regulating actin thin filament turnover.
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Thesis (Ph.D.)-- Wichita State University, College of Liberal Arts and Sciences, Dept. of Chemistry
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Wichita State University
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2020 by Vinay Kumar Kadarla
All Rights Reserved