Biology subjects

Tan, K. Y.

Publications and source records attributed to Tan, K. Y..

3 recordsLinked to original sources

bioRxiv2025

Antigenic Divergence of Cobra Short-chain α-Neurotoxins: Implications for Regional Antivenom Effectiveness in Southeast Asia

Short-chain -neurotoxins (SNTXs) are the principal neurotoxic components in several Asiatic cobras, including Naja atra, Naja philippinensis, and N. samarensis. Although structurally conserved, SNTXs exhibit marked antigenic variation that can limit the effectiveness of regional antivenoms used for snakebite envenoming in Asia. Here, we evaluated the immunoreactivity of the Philippine Cobra Antivenom (PCAV) and three regional products--Naja kaouthia Monovalent Antivenom (NkMAV), Neuro Bivalent Antivenom (NBAV), and Indonesian SABU--against a panel of cobra venoms and purified -neurotoxins. PCAV bound strongly to homologous N. philippinensis SNTX but showed weak cross-reactivity with SNTXs from N. kaouthia, N. sputatrix, and N. atra, and minimal recognition of marine elapid SNTXs and long-chain -neurotoxins (LNTXs) of Monocled Cobra as well as King Cobra. Conversely, NkMAV and NBAV recognized mainland Asian SNTXs more broadly but reacted poorly with the Philippine cobra toxin. Hierarchical clustering of normalized immunoreactivity delineated two major SNTX antigenic subtypes corresponding to Philippine versus continental Asian lineages. Peptide sequence analysis unmasked two distinct loop-II motifs (28WWS-TII37 and 28RWR-YRT37) associated with these divergent immunotypes. Phylogenetic reconstruction suggests that the Philippine cobras retain an ancestral SNTX motif, while Sundaic and East Asian cobras have diversified to employ another major SNTX form. Epitope prediction further revealed differences in surface exposure and accessibility that help explain the limited cross-neutralization across antivenoms. These findings demonstrate a clear antigenic dichotomy among Asian cobra SNTXs, which underlies species-specific antivenom effectiveness and highlights the need to incorporate representative SNTX variants into immunogen formulations to improve regional antivenom coverage.

biochemistry↗

bioRxiv2025

A conserved long-range RNA interaction in SARS-CoV-2 recruits ADAR1 to enhance virus proliferation

Long-range RNA-RNA pairing impacts the genome structure and function of SARS-CoV-2 variants. To understand the structure and function relationships of different SARS-CoV-2 variants that have emerged during the COVID-19 pandemic, we performed high-throughput structure probing and modelling of the genomic structures of the wildtype (WT), Alpha, Beta, Delta and Omicron variants of SARS-CoV-2. We observed that genomes of SARS-CoV-2 variants are generally structurally conserved, and that single-nucleotide variations and interactions with RNA binding proteins can impact RNA structures across the viruses. Importantly, using proximity ligation sequencing, we identified many conserved ultra-long-range RNA-RNA interactions, including one that spans more than 17 kb in both the WT virus and the Omicron variant. We showed that mutations that disrupt this 17 kb long-range interaction reduce viral fitness at later stages of its infection cycle, while compensatory mutations partially restore virus fitness. Additionally, we showed that this ultra-long-range RNA-RNA interaction structure binds directly to ADAR1 to alter the RNA editing levels on the viral genome. These studies deepen our understanding of RNA structures in the SARS-CoV-2 genome and their ability to interact with host factors to facilitate virus infectivity.

genomics↗

bioRxiv2021

Comprehensive mapping of SARS-CoV-2 interactions in vivo reveals functional virus-host interactions

SARS-CoV-2 has emerged as a major threat to global public health, resulting in global societal and economic disruptions. Here, we investigate the intramolecular and intermolecular RNA interactions of wildtype (WT) and a mutant ({Delta}382) SARS-CoV-2 virus in cells using high throughput structure probing on Illumina and Nanopore platforms. We identified twelve potentially functional structural elements within the SARS-CoV-2 genome, observed that identical sequences can fold into divergent structures on different subgenomic RNAs, and that WT and {Delta}382 virus genomes can fold differently. Proximity ligation sequencing experiments identified hundreds of intramolecular and intermolecular pair-wise interactions within the virus genome and between virus and host RNAs. SARS-CoV-2 binds strongly to mitochondrial and small nucleolar RNAs and is extensively 2-O-methylated. 2-O-methylation sites in the virus genome are enriched in the untranslated regions and are associated with increased pair-wise interactions. SARS-CoV-2 infection results in a global decrease of 2-O-methylation sites on host mRNAs, suggesting that binding to snoRNAs could be a pro-viral mechanism to sequester methylation machinery from host RNAs towards the virus genome. Collectively, these studies deepen our understanding of the molecular basis of SARS-CoV-2 pathogenicity, cellular factors important during infection and provide a platform for targeted therapy.

genomics↗