Protein interactions are primary determinants of function in living systems. Functional regulation can be achieved through changes in protein interactions resultant from mutations, altered protein abundance levels, posttranslational modifications, conformational changes or altered protein localization. The importance of the protein interaction network for understanding cellular function has long been primary motivation for its mapping. However, the concept of an ?edgotype? has more recently arisen to describe the protein interaction network where nodes are proteins, edges represent interactions and edge-level changes, or edgetic perturbations, define an edgotype resultant from genetic mutations. While genetic mutations are critical for stable phenotype definition, most drugs target proteins and alter one or more of the categories; abundance, modifications, conformation, or localization of target, downstream and off-target proteins. This project will focus efforts to extend the edgotype concept using a general mass spectrometry-based approach to visualize large-scale pharmacological effects on protein structures and interactions in cells to significantly advance cell- based pharmacological studies.

Public Health Relevance

Proteins are functional molecules critical to nearly all cellular processes involved in disease and normal healthy states and are targets of many pharmacological agents. Most molecular therapies result in altered protein structures, activities, and molecular interactions in cells. This project will identify in vivo structural features and molecular interactions that are altered during treatment of cancer cells with a variety of chemotherapies.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Drug Discovery and Molecular Pharmacology Study Section (DMP)
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Wu, Mary Ann
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University of Washington
Schools of Medicine
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Chavez, Juan D; Lee, Chi Fung; Caudal, Arianne et al. (2018) Chemical Crosslinking Mass Spectrometry Analysis of Protein Conformations and Supercomplexes in Heart Tissue. Cell Syst 6:136-141.e5
Vreven, Thom; Schweppe, Devin K; Chavez, Juan D et al. (2018) Integrating Cross-Linking Experiments with Ab Initio Protein-Protein Docking. J Mol Biol 430:1814-1828
Xu, Li; Gordon, Ryan; Farmer, Rebecca et al. (2018) Precision therapeutic targeting of human cancer cell motility. Nat Commun 9:2454
Park, Sung-Gun; Anderson, Gordon A; Bruce, James E (2018) Parallel detection in a single ICR cell: Spectral averaging and improved S/N without increased acquisition time. Int J Mass Spectrom 427:29-34
Mohr, Jared P; Perumalla, Poorna; Chavez, Juan D et al. (2018) Mango: A General Tool for Collision Induced Dissociation-Cleavable Cross-Linked Peptide Identification. Anal Chem 90:6028-6034
Chavez, Juan D; Bruce, James E (2018) Chemical cross-linking with mass spectrometry: a tool for systems structural biology. Curr Opin Chem Biol 48:8-18
Zhong, Xuefei; Navare, Arti T; Chavez, Juan D et al. (2017) Large-Scale and Targeted Quantitative Cross-Linking MS Using Isotope-Labeled Protein Interaction Reporter (PIR) Cross-Linkers. J Proteome Res 16:720-727
Kaufman, Daniel M; Wu, Xia; Scott, Barbara A et al. (2017) Ageing and hypoxia cause protein aggregation in mitochondria. Cell Death Differ 24:1730-1738
Schweppe, Devin K; Chavez, Juan D; Lee, Chi Fung et al. (2017) Mitochondrial protein interactome elucidated by chemical cross-linking mass spectrometry. Proc Natl Acad Sci U S A 114:1732-1737
Nygren, Patrick J; Mehta, Sohum; Schweppe, Devin K et al. (2017) Intrinsic disorder within AKAP79 fine-tunes anchored phosphatase activity toward substrates and drug sensitivity. Elife 6:

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