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Identification of Phosphorylase Kinase Alpha Subunit Binding Partners in Skeletal Muscle Soleil Archila

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Identification of Phosphorylase Kinase Alpha Subunit Binding Partners in Skeletal Muscle Soleil Archila Western Kentucky University TopSCHOLAR® Masters Theses & Specialist Projects Graduate School 2004 Identification of Phosphorylase Kinase Alpha Subunit Binding Partners in Skeletal Muscle Soleil Archila Follow this and additional works at: http://digitalcommons.wku.edu/theses Part of the Biochemistry, Biophysics, and Structural Biology Commons Recommended Citation Archila, Soleil, "Identification of Phosphorylase Kinase Alpha Subunit Binding Partners in Skeletal Muscle" (2004). Masters Theses & Specialist Projects. Paper 1108. http://digitalcommons.wku.edu/theses/1108 This Thesis is brought to you for free and open access by TopSCHOLAR®. It has been accepted for inclusion in Masters Theses & Specialist Projects by an authorized administrator of TopSCHOLAR®. For more information, please contact [email protected]. IDENTIFICATION OF PHOSPHORYLASE KINASE ALPHA SUBUNIT BINDING PARTNERS IN SKELETAL MUSCLE A Thesis Presented to the Faculty of the Department of Biology Western Kentucky University Bowling Green, Kentucky In Partial Fulfillment of the Requirements for the Degree Master of Science by Soleil Archila August 2004 IDENTIFICATION OF PHOSPHORYLASE KINASE ALPHA SUBUNIT BINDING PARTNERS IN SKELETAL MUSCLE Date Recommended: August 12, 2004 Nancy A. Rice, Director of Thesis Sigrid Jacobshagen Claire A. Rinehart Elmer Gray, Dean of Graduate Studies and Research, August 13, 2004 ACKNOWLEDGEMENTS There are many people to acknowledge for their direct or indirect contributions to my work. I would like to thank my advisor Dr. Nancy Rice for the guidance, educational enrichment, encouragement, kindness, and patience she provided me. I would also like to acknowledge the members of my committee, Dr. Sigrid Jacobshagen and Dr. Claire Rinehart not only for their guidance, but also for the educational enrichment they have provided me as well. Next, I would like to thank Dr. Gerald Carlson from the University of Kansas Medical Center for allowing us to collaborate with his laboratory. To the faculty and staff of the department of Biology I would like to express my gratitude for their support, particularly to Dr. Richard Bowker. I want to thank Dr. John Andersland and the staff of the Biotechnology Center for their assistance. I would like to acknowledge Ms. Kaneia Creek for her assistance in administrative issues. I would like to thank Dr. Cheryl Davis and Dr. Keith Philips for their support and friendship. To the staff of Graduate Studies and Research, I would like to express my gratitude as well, in particular to Ms. Robin Fulkerson, and especially to Dr. Elmer Gray and Dr. Lisa Murrell for their support and kindness. Lastly, I would like to express my deepest gratitude to my family. To my parents for always believing in me and for their sacrifices. To my uncle Rolando for having faith in me and always providing me support. I would like to dedicate this work to my grandmother, Mercedes (r.i.p.) for her dedication to the Archila family in providing love, unity and encouragement to succeed. God has blessed us for making her the foundation of what we have become. iii TABLE OF CONTENTS PAGES INTRODUCTION…………………………………………………. 9-24 MATERIALS AND METHODS……………………………….…. 25-34 RESULTS…………………………………………………………... 35-53 DISCUSSION………………………………………………………. 54-61 REFERENCES…………………………………………………….. 62-67 iv LIST OF FIGURES FIGURE PAGE 1.1 PhK Structure 12 1.2 The yeast two-hybrid system 18 1.3 Localization of the C-terminus of PhKα 24 2.1 pLexA plasmid map 26 2.2 pB42BD plasmid map 27 2.3 p8op-LacZ plasmid map 28 3.1 Putative positive interactions 36 3.2 cDNA library insert size determination 39 3.3 Elimination of redundant clones 41 3.4 Interaction specificity tests 42 3.5 SH3 domain in TRIP10 44 3.6 TPR domain in TPR1 46 3.7 Affinity of interactions with TRIP10 49 3.8 Affinity of interactions with TPR1 53 v LIST OF TABLES TABLE PAGE 3.1 β-Galactosidase expression as observed by yeast phenotype 38 3.2 Thyroid receptor interacting protein 10 (TRIP10) amino acid sequence alignments 45 3.3 Tetratricopeptide repeat protein 1 (TPR1) amino acid sequence alignments 47 vi IDENTIFICATION OF PHOSPHORYLASE KINASE ALPHA SUBUNIT BINDING PARTNERS IN SKELETAL MUSCLE Soleil Archila August 2004 67 Pages Directed by: Nancy A. Rice, Sigrid Jacobshagen, and Claire A. Rinehart Department of Biology Western Kentucky University Phosphorylase kinase (PhK) integrates neural, hormonal, and metabolic signals in skeletal muscle to tightly regulate glycogen breakdown and energy production. Structurally, PhK is among the largest and most complex kinases known with a stoichiometry of (αβγδ)4 and a mass of 1.3x106 Da. The catalytic γ subunit is allosterically controlled through alterations in quaternary structure initiated by the regulatory α, β and δ subunits. In this study we have chosen to examine the largest regulatory subunit, α. In addition to participating in intramolecular interactions within PhK, α is hypothesized to associate extrinsically with skeletal muscle proteins due to its peripheral location in the holoenzyme. To identify potential muscle protein interactors, the C-terminus of α , amino acid residues 1060-1237, was screened against a rabbit skeletal muscle cDNA library via a yeast two-hybrid assay. Interactions were selected by auxotrophic growth of yeast in the absence of leucine and by expression of β-galactosidase activity. Thirty- seven potential positive clones were initially observed. Secondary selections resulted in 13 putative clones being isolated of which 8 were identified as thyroid hormone receptor interacting protein 10 (TRIP10). TRIP10, also known as Cdc42 interacting protein 4 (CIP4), is highly expressed in skeletal muscle and is thought to act as a regulator of the actin cytoskeleton. The remaining 5 clones were identified as tetratricopeptide repeat protein 1 (TPR1). TPR1 is an adaptor protein that functions in a wide array of cellular processes and is considered a highly vii specific adaptor. The results reported herein are intriguing given that PhK is associated with the sarcoplasmic reticulum in the A-band / actin filament overlap zone and has previously been shown to interact with the thin filament protein nebulin. To our knowledge, this is the first report to identify TRIP10 as a potential sarcomeric protein, and these findings further suggest a role for PhK in muscle assembly and architecture. viii CHAPTER I INTRODUCTION Phosphorylase Kinase Phosphorylase kinase (PhK) was the first protein kinase discovered and belongs to a large family of well-known serine-threonine kinases. Studies on PhK led to the discovery of covalent modification of proteins occur via phosphorylation. PhK is among the largest and most complex enzymes known with a molecular weight of 1.3x106 daltons. PhK is a hexadecamer made up of four different subunits α, β, γ and δ. It is involved in the metabolic process of glycogen breakdown by regulating the activation of glycogen phosphorylase to degrade glycogen to glucose-1-phosphate (Pickett-Gies and Walsh, 1986). PhK regulation lies at the interface of hormonal, neural and metabolic extracellular signals. Hormones that are involved in regulation of carbohydrate metabolism and electrical signals involved in muscle contraction are examples of the signals that regulate PhK (Heilmeyer, 1991). Other allosteric effectors of PhK include ADP, Mg2+, ATP, Ca2+ /calmodulin, pH, and proteolysis (Pickett-Gies and Walsh, 1986) (Heilmeyer et al., 1992). Additionally, PhK is regulated by protein kinase A (PKA), a cAMP dependent kinase, that phosphorylates PhK on the α and β subunits increasing the specificity of PhK’s phosphotransferase activity response in the catalytic subunit. The availability of Ca2+ and phosphorylation by PKA cooperatively increase PhK’s activity, thus making the latter a point of cross-talk for two important signal transduction pathways (Brushia and Walsh, 1999). Calcium availability stimulates muscle contraction. Moreover, this signaling also integrates glycogen breakdown for energy availability. By these means PhK is able to serve at the interface of energy supply and demand (Owen et al., 1995). In 9 10 skeletal muscle PhK can be activated by troponin C, a protein homologous to calmodulin which exists at high levels in muscle, and such leads to the notion that the former may be the actual physiological regulator of PhK (Brushia and Walsh, 1999). PhK is expressed in both liver and skeletal muscle, and the muscle isoform is found in two different cellular compartments. The majority of the enzyme is located in the cytosol in association with glycogen phosphorylase and glycogen particles, thus the action of PhK on the former initiates glycogenolysis to satisfy energy demands for muscle contraction. Moreover, a smaller portion of PhK in muscle cells is associated with the sarcoplasmic reticulum (SR) membrane (Heilmeyer et al., 1992) (Thieleczek et al., 1987). Studies of immunological localization found that the four subunits were located at the sarcolemma and the SR, more specifically associated with the T tubule at the surface of terminal cisternae (Heilmeyer et al., 1992) (Georgoussi and Heilmeyer, 1986). The SR is involved in muscle contraction, specifically, in skeletal muscle it exists in significant amounts and serves as storage for Ca2+. The release of Ca2+ from the SR is a key activator for the contraction process (Schwartz et al., 1976) (Van Winkle and Entman, 1979). Therefore, the glycogenolysis process is triggered by this release of Ca2+ from the SR making the breakdown of glycogen contraction dependent in muscle
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