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Woo, Christina

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Woo

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Christina

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Woo, Christina
Author's Publications: search.filters.isAuthorOfPublication.02e54075-9cfc-4f62-b577-20fe93378a20

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    Mapping the Small Molecule Interactome by Mass Spectrometry
    (American Chemical Society (ACS), 2017-11-10) Flaxman, Hope; Woo, Christina
    Mapping small molecule interactions throughout the proteome provides the critical structural basis for functional analysis of their impact on biochemistry. However, translation of mass spectrometry-based proteomics methods to directly profile the interaction between a small molecule and the whole proteome is challenging because of the substoichiometric nature of many interactions, the diversity of covalent and noncovalent interactions involved, and the subsequent computational complexity associated with their spectral assignment. Recent advances in chemical proteomics have begun fill this gap to provide a structural basis for the breadth of small molecule–protein interactions in the whole proteome. Innovations enabling direct characterization of the small molecule interactome include faster, more sensitive instrumentation coupled to chemical conjugation, enrichment, and labeling methods that facilitate detection and assignment. These methods have started to measure molecular interaction hotspots due to inherent differences in local amino acid reactivity and binding affinity throughout the proteome. Measurement of the small molecule interactome is producing structural insights and methods for probing and engineering protein biochemistry. Direct structural characterization of the small molecule interactome is a rapidly emerging area pushing new frontiers in biochemistry at the interface of small molecules and the proteome.
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    Synthesis of an electronically-tuned minimally interfering alkynyl photo-affinity label to measure small molecule–protein interactions
    (Elsevier BV, 2018-06) Chang, Chia-fu; Mfuh, Adelphe; Gao, Jinxu; Wu, Hung-Yi; Woo, Christina
    We report the synthesis of an electronically-tuned minimally interfering photo-affinity label (MI-PAL), a compact five-carbon tag functionalized with an alkyl diazirine and alkyne handle. MI-PAL is compatible with protein photo-conjugation, click chemistry and mass spectrometry and readily installed to complex molecules for biological target identification.
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    The E3 ligase adapter cereblon targets the C-terminal cyclic imide degron
    (Springer Science and Business Media LLC, 2022-10-19) Ichikawa, Saki; Flaxman, Hope A.; Xu, Wenqing; Vallavoju, Nandini; Lloyd, Hannah C.; Wang, Binyou; Shen, Dacheng; Pratt, Matthew R.; Woo, Christina
    The E3 ligase substrate adaptor cereblon (CRBN) is a target of thalidomide and lenalidomide,1 which are therapeutic agents used in the treatment of hematopoietic malignancies2-4 and as ligands for targeted protein degradation.5-7 These agents are proposed to mimic a naturally occurring degron; however, the structural motif recognized by the thalidomide-binding domain of CRBN is unknown. Here, we report that C-terminal cyclic imides, overlooked post-translational modifications that arise from intramolecular cyclization of glutamine or asparagine residues, are physiological degrons on substrates for CRBN. Dipeptides bearing the C-terminal cyclic imide degron are substitutes for thalidomide when embedded within bifunctional chemical degraders. Installation of the degron to the C-terminus of proteins induces CRBN-dependent ubiquitination and degradation in vitro and in cells. C-Terminal cyclic imides form adventitiously on physiologically relevant timescales throughout the human proteome to afford a degron that is endogenously recognized and removed by CRBN. The discovery of the C-terminal cyclic imide degron defines a novel regulatory process that may impact the physiological function and therapeutic engagement of CRBN.
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    The Schizophrenia-Associated Variant in SLC39A8 Alters Protein Glycosylation in the Mouse Brain
    (Springer Science and Business Media LLC, 2022-03-08) Mealer, Robert; Williams, Sarah E.; Noel, Maxence; Yang, Bo; D'Souza, Alexandria; Nakata, Toru; Graham, Daniel B.; Creasey, Elizabeth A.; Cetinbas, Murat; Sadreyev, Ruslan; Scolnick, Edward; Woo, Christina; Smoller, Jordan; Xavier, Ramnik; Cummings, Richard
    A missense mutation (A391T) in the manganese transporter SLC39A8 is strongly associated with schizophrenia in genomic studies, though the molecular connection to the brain remains hypothetical. Human carriers of A391T have reduced serum manganese, altered plasma glycosylation, and brain MRI changes consistent with altered metal transport. Here, using a knock-in mouse model homozygous for A391T, we show that the schizophrenia-associated variant changes protein glycosylation in the brain. Glycosylation of Asn residues in glycoproteins (N-glycosylation) was most significantly impaired, with effects differing between regions. RNAseq analysis showed negligible regional variation, consistent with changes in the activity of glycosylation enzymes rather than gene expression. Finally, nearly one third of detected glycoproteins were differentially N-glycosylated in the cortex, including members of several pathways previously implicated in schizophrenia such as cell adhesion molecules and neurotransmitter receptors, and expressed across all cell types. These findings provide a mechanistic link between a risk allele and potentially reversible biochemical changes in the brain, furthering our molecular understanding of the pathophysiology of schizophrenia and a novel opportunity for therapeutic development.