Biology subjects

Chan, J. Y.

Publications and source records attributed to Chan, J. Y..

5 recordsLinked to original sources

bioRxiv2022

SARS-CoV-2 Omicron BA.2.12.1, BA.4, and BA.5 subvariants evolved to extend antibody evasion

SARS-CoV-2 Omicron subvariants BA.2.12.1 and BA.4/5 have surged dramatically to become dominant in the United States and South Africa, respectively1,2. These novel subvariants carrying additional mutations in their spike proteins raise concerns that they may further evade neutralizing antibodies, thereby further compromising the efficacy of COVID-19 vaccines and therapeutic monoclonals. We now report findings from a systematic antigenic analysis of these surging Omicron subvariants. BA.2.12.1 is only modestly (1.8-fold) more resistant to sera from vaccinated and boosted individuals than BA.2. However, BA.4/5 is substantially (4.2-fold) more resistant and thus more likely to lead to vaccine breakthrough infections. Mutation at spike residue L452 found in both BA.2.12.1 and BA.4/5 facilitates escape from some antibodies directed to the so-called class 2 and 3 regions of the receptor-binding domain3. The F486V mutation found in BA.4/5 facilitates escape from certain class 1 and 2 antibodies but compromises the spike affinity for the viral receptor. The R493Q reversion mutation, however, restores receptor affinity and consequently the fitness of BA.4/5. Among therapeutic antibodies authorized for clinical use, only bebtelovimab retains full potency against both BA.2.12.1 and BA.4/5. The Omicron lineage of SARS-CoV-2 continues to evolve, successively yielding subvariants that are not only more transmissible but also more evasive to antibodies.

microbiology↗

bioRxiv2022

Crystal structure of the Rubella virus protease reveals a unique papain-like protease fold

Rubella is well-controlled due to an effective vaccine, but outbreaks are still occurring without any available antiviral treatments. There is still much to learn about the rubella virus (RUBV) papain-like protease (RubPro) that could be a potential drug target. This protease is crucial to RUBV replication, cleaving the non-structural polyprotein p200 into 2 multi-functional proteins, p150 and p90. Here we report a novel crystal structure of RubPro at 1.64 [A] resolution. It has a similar catalytic core structure to that of SARS-CoV-2 and foot-mouth-disease virus (FMDV) proteases. RubPro has well-conserved sequence motifs that are also found in its newly discovered Rubivirus relatives. The RubPro construct was shown to have protease activity in trans against a construct of RUBV protease-helicase and fluorogenic peptide. A protease-helicase construct was also cleaved in E. coli expression. RubPro was demonstrated to possess deubiquitylation activity, suggesting a potential role of RubPro in modulating the hosts innate immune responses. The structural and functional insights of the RubPro will advance our current understanding of its function and point to more structure-based research into the RUBV replication machinery, in hopes of developing antiviral therapeutics in the future.

microbiology↗

bioRxiv2021

The C. elegans Notch proteins LIN-12 and GLP-1 are tuned to lower force thresholds for activation than Drosophila Notch

The conserved transmembrane receptor Notch mediates cell fate decisions in all animals. In the absence of ligand, a Negative Regulatory Region (NRR) in the Notch ectodomain adopts an autoinhibited confirmation, masking an ADAM protease cleavage site [1, 2]; ligand binding makes the cleavage site accessible, leading to shedding of the Notch ectodomain as the first step of signal transduction [3, 4]. In Drosophila and vertebrates, the ligands are all single-pass transmembrane Delta/Serrate/LAG-2 (DSL) proteins; the endocytic adaptor Epsin binds to the ubiquitinated intracellular domain, and the resulting Clathrin-mediated endocytosis exerts a "pulling force" that exposes the cleavage site in the NRR [4-6]. However, in C. elegans, the presence of natural secreted DSL proteins [7] and other observations suggested that Epsin-mediated endocytosis may not be required to activate the Notch proteins LIN-12 and GLP-1. Here, we confirm that neither Epsin nor the cytosolic domains of DSL proteins are required for Notch signaling in C. elegans. Furthermore, we provide evidence that the NRRs of LIN-12 and GLP-1 are tuned to a lower force level than the NRR of Drosophila Notch. Finally, we show that adding a Leucine "plug" that occludes the cleavage site in vertebrate and Drosophila Notch proteins but is absent in the C. elegans Notch proteins [1, 2] renders the LIN-12 and GLP-1 NRRs dependent on Epsin-mediated ligand endocytosis, indicating that greater force is now required to expose the cleavage site. Thus, the NRRs of LIN-12 and GLP-1 appear to be tuned to a lower force threshold, accounting for the different requirements for signaling in C. elegans.

developmental biology↗

bioRxiv2019

A Quantitative Proteome Map of the Human Body

Determining protein levels in each tissue and how they compare with RNA levels is important for understanding human biology and disease as well as regulatory processes that control protein levels. We quantified the relative protein levels from 12,627 genes across 32 normal human tissue types prepared by the GTEx project. Known and new tissue specific or enriched proteins (5,499) were identified and compared to transcriptome data. Many ubiquitous transcripts are found to encode highly tissue specific proteins. Discordance in the sites of RNA expression and protein detection also revealed potential sites of synthesis and action of protein signaling molecules. Overall, these results provide an extraordinary resource, and demonstrate that understanding protein levels can provide insights into metabolism, regulation, secretome, and human diseases.\n\nSummaryQuantitative proteome study of 32 human tissues and integrated analysis with transcriptome data revealed that understanding protein levels could provide in-depth knowledge to post transcriptional or translational regulations, human metabolism, secretome, and diseases.

systems biology↗

bioRxiv2018

Liquid biopsy in gastrointestinal stromal tumors -- Simultaneous detection of primary and secondary mutations with an NGS based circulating tumor DNA assay

Introduction Introduction Methods Results Discussion References Gastrointestinal Stromal tumors (GISTs) are the most common neoplasms of mesenchymal origin arising from the gastrointestinal tract. GISTs are mostly characterised by one predominant activating mutation in KIT (KIT proto-oncogene receptor tyrosine kinase) or PDGFRA (platelet derived growth factor receptor alpha) genes1-3. Under pharmacological pressure, one or more secondary mutations can develop in KIT, conferring resistance to tyrosine kinase inhibitor, imatinib. In imatinib-resistant GISTs, secondary mutations can occur in the ATP binding pocket, encoded by exons 13 and 14 or in the kinase activation loop, encoded predominantly by exon 174. In vitro studies ha ...

molecular biology↗