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CH-Π Interactions Play a Central Role in Protein Recognition of Carbohydrates

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CH-Π Interactions Play a Central Role in Protein Recognition of Carbohydrates CH-π interactions play a central role in protein recognition of carbohydrates by Roger Christopher Diehl B.S. Biochemistry University of Wisconsin-Madison, 2012 M.S. Biochemistry University of Wisconsin-Madison, 2017 SUBMITTED TO THE DEPARTMENT OF CHEMISTRY IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN CHEMISTRY AT THE MASSACHUSETTS INSTITUTE OF TECHNOLOGY February 2021 ©2021 Massachusetts Institute of Technology. All rights reserved. Signature of Author:____________________________________________________ Department of Chemistry January 15, 2021 Certified by:_________________________________________________________ Laura L. Kiessling Novartis Professor of Chemistry Thesis Supervisor Accepted by:_________________________________________________________ Adam Willard Associate Professor Graduate Officer 1 This doctoral thesis has been examined by a committee of the Department of Chemistry as follows: Professor Barbara Imperiali…………………………………………………………………………………………………. Thesis Committee Chair Class of 1922 Professor of Chemistry and Biology Professor Laura L. Kiessling…………………………………………………………………………………………………. Thesis Supervisor Novartis Professor of Chemistry Professor Matthew D. Shoulders…………………………………………………………………………………………… Thesis Committee Member Assistant Professor of Chemistry 2 CH-π interactions play a central role in protein recognition of carbohydrates by Roger Christopher Diehl Submitted to the Department of Chemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy at the Massachusetts Institute of Technology Abstract Carbohydrate-protein interactions play a central role in biology, but knowledge of the forces underlying them is limited. Carbohydrates are generally hydrophilic and therefore present unique challenges in their recognition. One underappreciated force involved in carbohydrate-protein interactions is the CH-π interaction, an attractive interaction between the aliphatic protons of a carbohydrate and the π system of an aromatic ring. In this thesis, I examine the fundamental nature, strength, and biological significance of this interaction, largely in the context of a family of carbohydrate-binding proteins known as galectins. In Chapter 1, I review previous knowledge of the forces underlying carbohydrate-binding proteins and the forces they utilize to bind their ligands. In particular, I focus on CH-π interactions and galectins. In Chapter 2, I examine the forces that contribute to CH-π interactions in the context of carbohydrates and aromatic compounds in aqueous solution. I find the CH-π interaction to be electronic in nature, and demonstrate its selectivity between different carbohydrates. In Chapter 3, I determine the contribution of the CH-π interaction to the ligand binding of galectin-3, a human carbohydrate-binding protein of medical significance. The data demonstrate that the CH-π interaction accounts for a majority of the binding energy. In Chapter 4, I explore the biological implications of the CH-π interaction in galectin-3. I demonstrate that the CH-π interaction is critical for the biological activities of galectin-3. In Chapter 5, I propose several directions future researchers could take to extend this work. For three of four directions, I present the progress I have made during my studies. The work contained within this thesis demonstrates that CH-π interactions play a central role in protein-carbohydrate interactions at both a molecular level and a biological level. Understanding the CH-π interaction is key to explaining and predicting the activity of carbohydrate-binding proteins. Thesis Supervisor: Laura L. Kiessling Title: Novartis Professor of Chemistry 3 Acknowledgements This work was only possible due to the many wonderful mentors I have had throughout my growth and development as a scientist. I cannot name all of them here, but I will name some. To my parents Tim and Sita Diehl, thank you for all your support in raising me to be the man I am today. Of relevance to this work, thank you for encouraging my curiosity as a child and enabling me to pursue my dreams. To Professor Nancy A Rice at Western Kentucky University, thank you for giving me my first experience in a modern biochemistry laboratory at VAMPY 2005. Science has changed since then but my passion for it has not. To Ms. Lucy Organ at Hillsboro High School, thank you for helping me realize that chemistry in particular is my field of interest. I am still a proud chemist, and still a proud Burro. Professor Lauren Buchanan, thank you for making my first chemistry class of college enjoyable, and for helping me handle the stress of my first first-author paper. Professor M Thomas Record, thank you for taking me into your lab as a freshman and teaching me techniques and principles that serve me well to this day. Chapters 2 and 3 in particular greatly benefitted from your perspective. Dr. Emily J. Guinn, thank you for being the best graduate student mentor an undergraduate researcher could ask for. You knew of my potential as a scientist when I doubted it, and helped me build the confidence I needed to make it through graduate school. Your example is one I look to whenever I am called upon to teach a fellow scientist. Last but definitely not least, thank you Professor Laura L. Kiessling. Thank you for seven excellent years in your lab, and in particular for giving me the opportunity to design the projects in this thesis. You have placed great trust in me over these years, and I sincerely hope you feel that I have rewarded that trust. Thank you also for ensuring a positive workplace environment in Kiessling Lab, even as students and postdocs have come and gone and the lab has moved from Wisconsin to MIT. Science is never easy and it is of the utmost importance that it takes place in a supportive context. Finally, I would like to thank all of the members of Kiessling Group that I have worked with during my time as a graduate student. All of you have been wonderful colleagues, and have helped me learn a broad array of disciplines and techniques ranging from vaccine development to reverse phase high-pressure liquid chromatography. I would particularly like to thank two subsets of Kiessling Group members. First, I would like to thank Dr. Christine Isabella, Dr. Alex Justen, Dr. Cassie Jarvis, and Professor Caitlin McMahon for organizing the move to MIT. It was an unforgettable experience and you four were key in making sure it proceeded as smoothly as possible. Second, I would like to thank Stephen Early, Melanie Halim, Alan Carter, Dr. Robert Brown, Dr. Mohammad Murshid Alam, Dr. R. Lyle McPherson, and Dr. Amanda Dugan for their contributions to the work in this thesis. Again, you have all been wonderful to work with. 4 Table of Contents Abstract………………………………………………………………………………………………………3 Acknowledgements………………………………………………………………………………………4 Table of Contents………………………………………………………………………………………….5 List of Tables and Schemes…………………………………………………………………………...7 List of Figures………………………………………………………………………………………………8 Chapter 1: Molecular Features of Lectin-Carbohydrate Interactions………………….10 Introduction…………………………………………………………………………………………………………11 Previously described features of carbohydrate-binding sites……………………………………..13 Previously described features of CH-π interactions…………………………………………………..15 Biophysical background regarding galectins…………………………………………………………….17 Biological background regarding galectins………………………………………………………………20 Conclusions and present work………………………………………………………………………………..22 References…………..……………………………………………………………………………………………….25 Chapter 2: Electronic Nature of CH-π Interactions………………………………………….36 Background and significance………………………………………………………………………………….37 Experimental section…………………………………………………………………………………………….38 1H NMR assay shows CH-π interactions in aqueous solution…………………………………….40 CH-π interactions between carbohydrates and aromatic groups are electronic in nature……………………………………………………………………………………………….43 CH-π interactions display selectivity between monosaccharides and anomers…………….45 Conclusions and future directions…………………………………………………………………………..48 Acknowledgements……………………………………………………………………………………………….50 References……………………………………………………………………………………………………………50 5 Chapter 3: A CH-π interaction drives glycan-binding to human galectin-3…………52 Background and significance………………………………………………………………………………….53 Galectin-3 bears a conserved tryptophan centrally located in the binding site…………….54 Materials and methods………………………………………………………………………………………….55 Galectin-3 variants are stable at room temperature………………………………………………….57 Galectin-3 variants have reduced binding affinity towards lactose…………………………….60 CH-π interactions account for the majority of binding energy in galectin-3………………..63 Acknowledgements……………………………………………………………………………………………….64 References……………………………………………………………………………………………………………64 Chapter 4: Biological functions of the CH-π interaction in galectin-3…………………67 Roles and structures of human galectins…………………………………………………………………68 Full-length galectin-3 variants have reduced agglutination activity towards mouse red blood cells…………………………………………………………………………………………….69 Wild-type galectin-3C binds to secreted mucins, but variants at W181 do not……………..71 Wild-type galectin-3 is exported from HEK-293 cells, while variants at W181 are retained in the cell………………………………………………………….73 Conclusions………………………………………………………………………………………………………….76 Acknowledgements………………………………………………………………………………………………..77 References…………………………………………………………………………………………………………….77 Chapter 5: Further Avenues for Investigation…………………………………………………80
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