Jonathan Yang

All Publications

• Charting a nanoscale map of the human cell surface proteome using proximity labeling proteomics Floyd, B. M., Schmidt, E., Till, N., Yang, J., Liao, P., George, B., Flynn, R., Bertozzi, C. ELSEVIER. 2025

  View details for Web of Science ID 001635831800067

• Mapping the nanoscale organization of the human cell surface proteome reveals new functional associations and surface antigen clusters. bioRxiv : the preprint server for biology Floyd, B. M., Schmidt, E. L., Till, N. A., Yang, J. L., Liao, P., George, B. M., Flynn, R. A., Bertozzi, C. R. 2025

  Abstract

  The cell surface is a dynamic interface that controls cell-cell communication and signal transduction relevant to organ development, homeostasis and repair, immune reactivity, and pathologies driven by aberrant cell surface phenotypes. The spatial organization of cell surface proteins is central to these processes. High-resolution fluorescence microscopy and proximity labeling have advanced studies of surface protein associations, but the spatial organization of the complete surface proteome remains uncharted. In this study, we systematically mapped the surface proteome of human T-lymphocytes and B-lymphoblasts using proximity labeling of 85 antigens, identified from over 100 antibodies tested for binding to surface-exposed proteins. These experiments were coupled with an optimized data-independent acquisition mass spectrometry workflow to generate a robust dataset. Unsupervised clustering of the resulting interactome revealed functional modules, including well-characterized complexes such as the T-cell receptor and HLA class I/II, alongside novel clusters. Notably, we identified mitochondrial proteins localized to the surface, including the transcription factor TFAM, suggesting previously unappreciated roles for mitochondrial proteins at the plasma membrane. A high-accuracy machine learning classifier predicted over 6,000 surface protein associations, highlighting functional associations such as IL10RB's role as a negative regulator of type I interferon signaling. Spatial modeling of the surface proteome provided insights into protein dispersion patterns, distinguishing widely distributed proteins, such as CD45, from localized antigens, such as CD226 pointing to active mechanisms of regulating surface organization. This work provides a comprehensive map of the human surfaceome and a resource for exploring the spatial and functional dynamics of the cell membrane proteome.

  View details for DOI 10.1101/2025.02.12.637979

  View details for PubMedID 40027624

  View details for PubMedCentralID PMC11870420

• Directed evolution of genetically encoded LYTACs for cell-mediated delivery. Proceedings of the National Academy of Sciences of the United States of America Yang, J. L., Yamada-Hunter, S. A., Labanieh, L., Sotillo, E., Cheah, J. S., Roberts, D. S., Mackall, C. L., Bertozzi, C. R., Ting, A. Y. 2024; 121 (13): e2320053121

  Abstract

  Lysosome-targeting chimeras (LYTACs) are a promising therapeutic modality to drive the degradation of extracellular proteins. However, early versions of LYTAC contain synthetic glycopeptides that cannot be genetically encoded. Here, we present our designs for a fully genetically encodable LYTAC (GELYTAC), making our tool compatible with integration into therapeutic cells for targeted delivery at diseased sites. To achieve this, we replaced the glycopeptide portion of LYTACs with the protein insulin-like growth factor 2 (IGF2). After showing initial efficacy with wild-type IGF2, we increased the potency of GELYTAC using directed evolution. Subsequently, we demonstrated that our engineered GELYTAC construct not only secretes from HEK293T cells but also from human primary T-cells to drive the uptake of various targets into receiver cells. Immune cells engineered to secrete GELYTAC thus represent a promising avenue for spatially selective targeted protein degradation.

  View details for DOI 10.1073/pnas.2320053121

  View details for PubMedID 38513100

• <i>gem</i>-Difluoroallylation of Aryl Halides and Pseudo Halides with Difluoroallylboron Reagents in High Regioselectivity ANGEWANDTE CHEMIE-INTERNATIONAL EDITION Sakamoto, S., Butcher, T. W., Yang, J. L., Hartwig, J. F. 2021; 60 (49): 25746-25752

  Abstract

  We report the palladium-catalyzed gem-difluoroallylation of aryl halides and pseudo halides with 3,3-difluoroallyl boronates in high yield with high regioselectivity, and we report the preparation of the 3,3-difluoroallyl boronate reactants by a copper-catalyzed defluorinative borylation of inexpensive gaseous 3,3,3-trifluoropropene with bis(pinacolato)diboron. The gem-difluoroallylation of aryl and heteroaryl bromides proceeds with low catalyst loading (0.1 mol % [Pd]) and tolerates a wide range of functional groups, including primary alcohols, secondary amines, ethers, ketones, esters, amides, aldehydes, nitriles, halides, and nitro groups. This protocol extends to aryl iodides, chlorides, and triflates, as well as substituted difluoroallyl boronates, providing a versatile synthesis of gem-difluoroallyl arenes that we show to be valuable intermediates to a series of fluorinated building blocks.

  View details for DOI 10.1002/anie.202111476

  View details for Web of Science ID 000711026700001

  View details for PubMedID 34555220

• Copper-Catalyzed Defluorinative Borylation and Silylation of <i>gem</i>-Difluoroallyl Groups ORGANIC LETTERS Butcher, T. W., Yang, J. L., Hartwig, J. F. 2020; 22 (17): 6805-6809

  Abstract

  Stereodefined (Z)-fluoroalkenes are bioisosteres of amides and synthetic precursors to value-added fluorinated compounds, but their stereoselective synthesis remains challenging. Herein, we report a copper-catalyzed formal SN2' defluorinative borylation of 3-substituted 3,3-difluoropropenes to form 3-fluoroallylboronic esters in high yields with excellent Z/E ratios. The primary 3-fluoroallylboronic esters undergo several synthetic sequences involving SE2' substitutions, SN2' substitutions, and sigmatropic rearrangements to provide tertiary allylic fluorides.

  View details for DOI 10.1021/acs.orglett.0c02321

  View details for Web of Science ID 000569377600023

  View details for PubMedID 32841569

  View details for PubMedCentralID PMC11620733

• Desymmetrization of difluoromethylene groups by C-F bond activation NATURE Butcher, T. W., Yang, J. L., Amberg, W. M., Watkins, N. B., Wilkinson, N. D., Hartwig, J. F. 2020; 583 (7817): 548-+

  Abstract

  Tertiary stereogenic centres containing one fluorine atom are valuable for medicinal chemistry because they mimic common tertiary stereogenic centres containing one hydrogen atom, but they possess distinct charge distribution, lipophilicity, conformation and metabolic stability1-3. Although tertiary stereogenic centres containing one hydrogen atom are often set by enantioselective desymmetrization reactions at one of the two carbon-hydrogen (C-H) bonds of a methylene group, tertiary stereocentres containing fluorine have not yet been constructed by the analogous desymmetrization reaction at one of the two carbon-fluorine (C-F) bonds of a difluoromethylene group3. Fluorine atoms are similar in size to hydrogen atoms but have distinct electronic properties, causing C-F bonds to be exceptionally strong and geminal C-F bonds to strengthen one another4. Thus, exhaustive defluorination typically dominates over the selective replacement of a single C-F bond, hindering the development of the enantioselective substitution of one fluorine atom to form a stereogenic centre5,6. Here we report the catalytic, enantioselective activation of a single C-F bond in an allylic difluoromethylene group to provide a broad range of products containing a monofluorinated tertiary stereogenic centre. By combining a tailored chiral iridium phosphoramidite catalyst, which controls regioselectivity, chemoselectivity and enantioselectivity, with a fluorophilic activator, which assists the oxidative addition of the C-F bond, these reactions occur in high yield and selectivity. The design principles proposed in this work extend to palladium-catalysed benzylic substitution, demonstrating the generality of the approach.

  View details for DOI 10.1038/s41586-020-2399-1

  View details for Web of Science ID 000623845100001

  View details for PubMedID 32480398

  View details for PubMedCentralID PMC10484566