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Multimodal Recognition of Diverse Peptides by the SH2 Domains of PLC1 and SH2B1

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Multimodal Recognition of Diverse Peptides by the SH2 Domains of PLC1 and SH2B1 i Multimodal Recognition of Diverse Peptides by the SH2 Domains of PLC1 and SH2B1 by Marissa A. McKercher B.S., Biology, University of Denver, 2007 B.S.Ch., Chemistry, University of Denver, 2007 A thesis submitted to the faculty of the Graduate School of the University of Colorado in partial fulfillment of the requirement for the degree of Doctor of Philosophy Department of Chemistry and Biochemistry University of Colorado, Boulder 2017 ii This thesis entitled: Multimodal Recognition of Diverse Peptides by the SH2 Domains of PLC1 and SH2B1 written by Marissa A. McKercher has been approved for the Department of Chemistry and Biochemistry Deborah S. Wuttke Joseph J. Falke Date The final copy of this thesis has been examined by the signatories, and we find that both the content and the form meet acceptable presentation standards of scholarly work in the above mentioned discipline. iii Thesis Statement McKercher, Marissa A. (Ph.D., Chemistry and Biochemistry) Multimodal Recognition of Diverse Peptides by the SH2 Domains of PLC1 and SH2B1 Thesis directed by Professor Deborah S. Wuttke SH2 domains recognize phosphotyrosine (pY)-containing peptide ligands and regulate a wide array of signaling events within receptor tyrosine kinase pathways. SH2 domains have individualized specificity for peptides, encoded in the amino acids neighboring the pY of the ligand. In contrast to this simple view of signaling specificity, high-throughput array studies have identified several SH2 domains capable of recognizing peptides containing chemically distinct amino acids at the positions neighboring the pY. For example, the C-terminal SH2 domain (PLCC) of phospholipase C-1 (PLC1) typically binds peptides containing small and hydrophobic amino acids adjacent to the pY, but can also recognize unexpected peptides containing amino acids with polar or bulky side chains that deviate from this pattern. Similarly, the SH2 domain of Src homology 2 B adaptor protein 1 (SH2B1) can recognize peptides containing either hydrophobic or acidic amino acids at the +3 position C-terminal to the pY. This multimodal specificity may enable these proteins to participate in diverse, previously unrecognized, signaling pathways in response to binding chemically dissimilar partners and facilitate their ability to act as signaling hubs. To better understand this multimodal specificity, we have used thermodynamic and structural approaches, including isothermal titration calorimetry (ITC), nuclear magnetic resonance (NMR), and X-ray crystallography, to elucidate the mechanisms of diverse peptide binding to PLCC and SH2B1. We have identified hydrophobic and charged residues that play distinct roles in peptide binding to each SH2 domain. High resolution crystal structures of PLCC iv and SH2B1 have also identified conformational plasticity within the peptide ligands of PLCC and within several loops of SH2B1, which appears to contribute to the ability of these domains to recognize diverse ligands. A better understanding of the adaptability of PLCC and SH2B1 will expand the ability of researchers to identify biological ligands of SH2 domains, and will be necessary for the rational development of small molecule therapeutics to target, and selectively inhibit, a desired SH2 domain/ligand interface. v Acknowledgements I would like to thank my advisor, Deborah Wuttke, for her constant guidance, patience, and enthusiasm. She continuously challenged me, and I am immensely grateful for her dedication to helping me grow as a scientific researcher, presenter, and writer. I cannot imagine having a better mentor. I am grateful to the entire Wuttke Lab and several members of the Pardi and Hough Labs, especially Neil Lloyd, Nicholas Parsonnet, Sabrina Hunt, and Kathryn Wall, for their helpful conversations and numerous troubleshooting suggestions. My committee members, Marcelo Sousa, Joe Falke, Loren Hough, and Michael Shirts also provided knowledge and advice that were invaluable to the development of my project. I would also like to thank David McKay, Annette Erbse, and Art Pardi for their outstanding X-ray crystallography, ITC, and NMR technical support, training, and experimental design suggestions. I am especially grateful to my friends, Sarah Dickerson, Katie Ferguson, Teri Andony, and Lauren Kelley, for offering me so much compassion and advice throughout the entire roller coaster ride of graduate school. Above all, I thank my husband, Ben Van Dehy, and my parents, Mark and Judy McKercher, for their endless encouragement, love, and coffee trips. I couldn’t have made it without such an amazing group of supporters. vi Contents 1. Introduction ............................................................................................................................... 1 1.1. SH2 Domains .......................................................................................................................... 1 1.1.1. Functional overview.......................................................................................................... 1 1.1.2. Discovery .......................................................................................................................... 1 1.1.3. Structure and ligand recognition ....................................................................................... 2 1.2. Structural Plasticity in Signaling Proteins .......................................................................... 6 1.2.1. Plasticity at signaling hubs................................................................................................ 6 1.2.2. Structural plasticity of SH2 domains in the recognition of singly and doubly phosphorylated peptides.............................................................................................................. 8 1.3. PLCC ..................................................................................................................................... 15 1.3.1. Domain architecture of the phospholipase C- (PLC) isozymes ................................... 15 1.3.2. Diverse functions of the PLC isozymes ........................................................................ 15 1.3.3. Medical relevance of PLC1 ........................................................................................... 17 1.3.4. Specificity profile of the C-terminal SH2 domain of PLC1 (PLCC) ............................ 17 1.3.5. Cognate binding mode of PLCC ..................................................................................... 19 1.3.6. Diversity in peptide ligand recognition........................................................................... 20 1.4 SH2B1..................................................................................................................................... 21 1.4.1 Domain architecture of SH2B1 ........................................................................................ 21 1.4.2 Function of SH2B1 .......................................................................................................... 23 1.4.3 Medical relevance of SH2B1 ........................................................................................... 24 1.4.4. Specificity profile of the SH2 domain of SH2B1 ........................................................... 26 1.4.5. Cognate binding mode of SH2B1 ................................................................................... 26 1.4.6. Diversity in peptide ligand recognition........................................................................... 28 2. Multimodal Recognition of Diverse Peptides by the C-Terminal SH2 Domain of PLC130 2.1. Introduction .......................................................................................................................... 30 2.2. Materials and Methods ........................................................................................................ 31 2.2.1. PLCC cloning, expression, and purification ................................................................... 31 vii 2.2.2. Circular dichroism .......................................................................................................... 32 2.2.3. Limited proteolysis ......................................................................................................... 32 2.2.4. Synthesis of peptides....................................................................................................... 33 2.2.5. Protein and peptide concentrations ................................................................................. 36 2.2.6. Isothermal titration calorimetry (ITC) ............................................................................ 37 2.2.7. Crystallization screening by sitting drop vapor diffusion ............................................... 37 2.2.7.a. Optimization of protein concentration, protein:peptide ratio, temperature, and buffer conditions for crystallization................................................................................................. 38 2.2.7.b. Volume scaling to promote the growth of sizeable crystals .................................... 39 2.2.8. Crystallization screening by hanging-drop vapor diffusion ............................................ 39 2.2.8.a. Crystal seeding ......................................................................................................... 40 2.2.9. X-ray data collection and refinement .............................................................................. 42 2.2.10. Structure data deposition..............................................................................................
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