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The Sequence and Function Relationship of Elastin: How The Sequence and Function Relationship of Elastin: How Repetitive Sequences Can Influence the Physical Properties of Elastin by David Yi Ming He A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Molecular Genetics University of Toronto © Copyright by David Yi Ming He 2011 ii The Sequence and Function Relationship of Elastin: How Repetitive Sequences Can Influence the Physical Properties of Elastin David Yi Ming He Doctor of Philosophy Molecular Genetics University of Toronto 2011 Abstract Elastin is an essential extracellular protein that is a key component of elastic fibres, providing elasticity to cardiac, dermal, and arterial tissues. During the development of the human cardiovascular system, elastin self-assembles before being integrated into fibres, undergoing no significant turnover during the human lifetime. Abnormalities in elastin can adversely affect its self-assembly, and may lead to malformed elastic fibres. Due to the longevity required of these fibres, even minor abnormalities may have a large cumulative effect over the course of a lifetime, leading to late-onset vascular diseases. This thesis project has identified important, over-represented repetitive elements in elastin which are believed to be important for the self- assembly and elastomeric properties of elastin. Initial studies of single nucleotide polymorphisms (SNPs) from the HapMap project and dbSNP resulted in a set of genetic variation sites in the elastin gene. Based on these studies, glycine to serine and lysine to arginine substitutions were introduced in elastin-like polypeptides. The self-assembly properties of the resulting elastin-like polypeptides were observed under microscope and measured using absorbance at 440nm. iii Assembled polypeptides were also cross-linked to form thin membranes whose mechanical and physical properties were measured and compared. These mutations resulted in markedly different behavior than wild-type elastin-like proteins, suggesting that mutations in the repetitive elements of the elastin sequence can lead to adverse changes in the physical and functional properties of the resulting protein. Using next-generation sequencing, patients with thoracic aortic aneurysms are being genotyped to discover polymorphisms which may adversely affect the self-assembly properties of elastin, providing a link between genetic variation in elastin and cardiovascular disease. iv Acknowledgments I would like to thank the Parkinson and Keeley laboratories for their tremendous help and support in both the computational and experimental components of this project. Special thanks to Eva and Megan for teaching me the laboratory skills I needed to get most of the data found in the third chapter of this thesis. I am also grateful for the invaluable help and advice provided by my committee members, Drs. Keeley and Zhang. For his super-human patience, and never-ending support during my entire PhD at UofT, I especially want to thank Dr. John Parkinson, without whom, I would have given up years ago. I would also like to thank my family, especially my parents who have always been my greatest fans. And lastly, I need to thank my new wife, Tiffany, who has supported me throughout my PhD study and even allowed me to mention elastin on our honeymoon. v Table of Contents Acknowledgments.......................................................................................................................... iv Table of Contents .............................................................................................................................v List of Tables ................................................................................................................................. ix List of Figures ..................................................................................................................................x Chapter 1 Introduction .....................................................................................................................1 1 Elastin ..........................................................................................................................................1 1.1 Elastin and Elastic Fibres .....................................................................................................3 1.2 The Importance of Elastin in Health and Disease ................................................................6 1.3 The Elastin Sequence ...........................................................................................................9 1.4 Characterization of Repetitive Elements in Elastin ...........................................................12 1.5 Elastin Structure .................................................................................................................14 1.6 Models of Elasticity ...........................................................................................................16 1.7 Coacervation ......................................................................................................................20 1.8 Lysyl Oxidase and Elastin Cross-link Formation ..............................................................22 1.9 Evolution of Elastin ...........................................................................................................25 1.10 Elastin-like Polypeptides ...................................................................................................29 1.11 Comparison of Elastin to Other Elastic Proteins ...............................................................30 1.11.1 Abductin .................................................................................................................31 1.11.2 Resilin ....................................................................................................................32 1.11.3 Wheat gluten protein ..............................................................................................32 1.11.4 Spider Silk Proteins................................................................................................33 1.12 Project Goals ......................................................................................................................33 Chapter 2 Survey of elastin sequence ............................................................................................36 2 Survey of elastin sequence ........................................................................................................36 vi 2.1 Introduction ........................................................................................................................36 2.2 Materials and Methods .......................................................................................................39 2.2.1 Collation of elastin sequence .................................................................................39 2.2.2 Sequence survey.....................................................................................................40 2.2.3 Motif identification and characterization ...............................................................41 2.2.4 Exon Evolution ......................................................................................................45 2.3 Results ................................................................................................................................47 2.3.1 Distribution of simple repeats in elastin ................................................................47 2.3.2 A graph based approach for the detection of functionally relevant motifs in elastin .....................................................................................................................51 2.3.3 Expansion of sequence motifs detected in elastin..................................................61 2.3.4 SubSeqer: a web -based motif finding tool ............................................................65 2.3.5 The role of domain expansions in the evolution of elastin ....................................67 2.4 Discussion ..........................................................................................................................76 2.4.1 Elastin motifs .........................................................................................................78 2.4.2 Subsequence network analysis of other low-complexity proteins .........................80 2.4.3 Domain evolution...................................................................................................83 Chapter 3 Effect of Mutations in repeats .......................................................................................87 3 Effect of Mutations in Repetitive Elements on the Physical Properties of Elastin-like Polypeptides ..............................................................................................................................87 3.1 Introduction ........................................................................................................................87 3.2 Materials and Methods .......................................................................................................90 3.2.1 Identification of Elastin Polymorphisms ...............................................................90 3.2.2 EP Construct Preparation .......................................................................................91 3.2.3 Protein expression and purification .......................................................................95 3.2.4 Circular Dichroism
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