Biology subjects

Yang, T.-J.

Publications and source records attributed to Yang, T.-J..

11 recordsLinked to original sources

bioRxiv2026

Global Sesame Germplasm Harbors Untapped Genetic Potential for Crop Improvement

Background Sesame (Sesamum indicum L.) is one of the oldest oilseed crops. Its seeds accumulate lignans and antioxidants that determine their nutritional value. Global demand for sesame is rising rapidly, but climate change increasingly threatens sesame yields and seed quality. Here, we analyzed a worldwide panel of 300 sesame accessions to explore the genetic basis of key adaptive and quality traits, specifically flowering time, seed lignan content, and seed antioxidant capacity. Results Whole-genome resequencing revealed previously unreported genetic diversity, expanding the resources available for sesame breeding. By integrating k-mer-based genome-wide association analysis with a graph-based sesame genome, we identified structural variants associated with differences in flowering time and lignan accumulation. A 9.4-kb deletion on chromosome 6 that disrupted SIN_1018434 (an ortholog of Arabidopsis PHOTOPERIOD-INDEPENDENT EARLY FLOWERING 1) and a 6.2-kb Copia-type retrotransposon insertion upstream of SIN_1004470 on chromosome 11 were associated with early flowering. The intact alleles at both loci were associated with delayed flowering and were predominant in low-latitude accessions. High seed lignan content was associated with non-synonymous mutations and copy number variants in glycosyl hydrolase genes on chromosome 6 and an 8.2-kb deletion spanning SIN_1019378 on chromosome 13. Association signals for seed antioxidant traits coincided with loci involved in abiotic stress responses and seed-coat pigmentation. Conclusions These findings highlight the importance of exploring diverse germplasm to uncover previously unrecognized adaptive and quality-associated genomic variation. The loci identified here provide molecular targets for developing climate-adapted cultivars with improved seed quality.

genomics↗

bioRxiv2025

SND3 is the membrane insertase within a fungal multipass translocon

During the biogenesis of most eukaryotic integral membrane proteins (IMPs), transmembrane domains are inserted into the endoplasmic reticulum membrane by a dedicated insertase or the SEC61 translocon. The SRP-independent (SND) pathway is the least understood route into the membrane, despite catering for a broad range of IMP types. Here, we show that Chaetomium thermophilum SND3 is a membrane insertase of novel fold. We further present a cryo-electron microscopy structure of a ribosome-associated SND3 translocon complex involved in co-translational IMP insertion. The structure reveals that the SND3 translocon additionally comprises the complete SEC61 translocon, CCDC47 and TRAP[a]. Here, the SEC61{beta} N-terminus works together with CCDC47 to prevent substrate access to the translocon. Instead, molecular dynamics simulations show that SND3 disrupts the lipid bilayer to promote IMP insertion via its membrane-embedded hydrophilic groove. Structural and sequence comparisons indicate that the SND3 translocon is a distinct multipass translocon for the insertion of multipass IMPs in fungi, euglenozoan parasites and other eukaryotic taxa.

biophysics↗

bioRxiv2025

Structures of Chaetomium thermophilum TOM complexes with bound preproteins

Mitochondria import most of their proteins from the cytoplasm through the TOM complex. Preproteins containing targeting signals are recognized by the TOM receptor subunits, and translocated by Tom40 across the outer mitochondrial membrane. We present four structures of the preprotein-bound and preprotein-free TOM core and holo complex from the thermophilic fungus Chaetomium thermophilum, obtained by single-particle electron cryomicroscopy. Our structures reveal the symmetric arrangement of two copies of the Tom20 receptor subunit in the TOM holo complex. Several different conformations of Tom20 within the TOM holo complex highlight the dynamic nature of the receptor. The structure of preprotein-bound Tom20 provides insight into the early stages of protein translocation.

biophysics↗

bioRxiv2022

Targeting Reductive Metabolic Shifts by T315I Mutation in BCR-ABL Myeloid Leukemia for Therapy

T315I mutation of Bcr-Abl in chronic myeloid leukemia (CML) leads to therapeutic resistance. It is known that Bcr-Abl transformation causes ROS-induced DNA damages and replication stress, which can be exploited for anti-nucleotide therapy. We developed a small compound, JMF4073, which inhibited pyrimidylate kinases and selectively eliminated Bcr-Abl-transformed, but not untransformed myeloid cells, due to dTTP exhaustion and ROS-induced replication stress. However, T315I-Bcr-Abl-transformed cells were less vulnerable to JMF4073 because of higher dTTP pool and low replication stress. Unlike WT-Bcr-Abl-transformed cells, T315I-Bcr-Abl cells lacked Sirt1- regulated OXPHOS with increased glutamine flux to reductive carboxylation in TCA cycle and glutathione synthesis. Blocking mitochondrial pyruvate carrier (MPC) by UK-5099 reduced NADH and glutathione levels with replication stress induction, thereby converting T315I-Bcr-Abl cells sensitive to JMF4073 with dTTP and dCTP depletion. The combination of JMF4073 with UK-5099 showed in vivo eradication of T315I-Bcr-Abl-CML. These data reveal that T315I mutation causes reductive metabolic shifts in Bcr-Abl-CML, and demonstrate the therapeutic option by co-targeting MPC and pyrimidylate kinases.

cancer biology↗

bioRxiv2021

A merger between compatible but divergent genomes supports allopolyploidization in the Brassicaceae family

Hybridization and polyploidization are pivotal to plant evolution. Genetic crosses between distantly related species rarely occur in nature mainly due to reproductive barriers but how such hurdles can be overcome is largely unknown. xBrassicoraphanus is a fertile intergeneric allopolyploid synthesized between Brassica rapa and Raphanus sativus in the Brassicaceae family. Genomes of B. rapa and R. sativus are diverged enough to suppress synapsis formation between non-homologous progenitor chromosomes during meiosis, and we found that both genomes reside in the single nucleus of xBrassicoraphanus without genome loss or rearrangement. Expressions of syntenic orthologs identified in B. rapa and R. sativus were adjusted to a hybrid nuclear environment of xBrassicoraphanus, which necessitates reconfiguration of transcription network by rewiring cis-trans interactions. B. rapa coding sequences have a higher level of gene-body methylation than R. sativus, and such methylation asymmetry is maintained in xBrassicoraphanus. B. rapa-originated transposable elements were transcriptionally silenced in xBrassicoraphanus, rendered by gain of CHG methylation in trans via small RNAs derived from the same sequences of R. sativus subgenome. Our work proposes that not only transcription compatibility but also a certain extent of genome divergence supports hybrid genome stabilization, which may explain great diversification and expansion of angiosperms during evolution.

plant biology↗

bioRxiv2021

Structure-activity relationships of B.1.617 and other SARS-CoV-2 spike variants

The surge of COVID-19 infection cases is spurred by emerging SARS-CoV-2 variants such as B.1.617. Here we report 38 cryo-EM structures, corresponding to the spike protein of the Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2) and Kappa (B.1.617.1) variants in different functional states with and without its receptor, ACE2. Mutations on the N-terminal domain not only alter the conformation of the highly antigenic supersite of the Delta variant, but also remodel the glycan shield by deleting or adding N-glycans of the Delta and Gamma variants, respectively. Substantially enhanced ACE2 binding was observed for all variants, whose mutations on the receptor binding domain modulate the electrostatics of the binding interfaces. Despite their abilities to escape host immunity, all variants can be potently neutralized by three unique antibodies.

biophysics↗

bioRxiv2021

Distinct shifts in site-specific glycosylation pattern of SARS-CoV-2 spike proteins associated with arising mutations in the D614G and Alpha variants

Extensive glycosylation of the spike protein of SARS-CoV-2 virus not only shields the major part of it from host immune responses, but glycans at specific sites also act on its conformation dynamics and contribute to efficient host receptor binding, and hence infectivity. As variants of concern arise during the course of the COVID-19 pandemic, it is unclear if mutations accumulated within the spike protein would affect its site-specific glycosylation pattern. The Alpha variant derived from the D614G lineage is distinguished from others by having deletion mutations located right within an immunogenic supersite of the spike N-terminal domain that make it refractory to most neutralizing antibodies directed against this domain. Despite maintaining an overall similar structural conformation, our mass spectrometry-based site-specific glycosylation analyses of similarly produced spike proteins with and without the D614G and Alpha variant mutations reveal a significant shift in the processing state of N-glycans on one specific N-terminal domain site. Its conversion to a higher proportion of complex type structures is indicative of altered spatial accessibility attributable to mutations specific to the Alpha variant that may impact its transmissibility. This and other more subtle changes in glycosylation features detected at other sites provide crucial missing information otherwise not apparent in the available cryogenic electron microscopy-derived structures of the spike protein variants.

biochemistry↗

bioRxiv2021

Impacts on the structure-function relationship of SARS-CoV-2 spike by B.1.1.7 mutations

The UK variant of the severe acute respiratory syndrome coronavirus (SARS-CoV-2), known as B.1.1.7, harbors several point mutations and deletions on the spike (s) protein, which potentially alter its structural epitopes to evade host immunity while enhancing host receptor binding. Here we report the cryo-EM structures of the S protein of B.1.1.7 in its apo form and in the receptor ACE2-bound form. One or two of the three receptor binding domains (RBDs) were in the open conformation but no fully closed form was observed. In the ACE-bound form, all three RBDs were engaged in receptor binding. The B.1.1.7-specific A570D mutation introduced a salt bridge switch that could modulate the opening and closing of the RBD. Furthermore, the N501Y mutation in the RBD introduced a favorable {pi}-{pi} interaction manifested in enhanced ACE2 binding affinity. The N501Y mutation abolished the neutralization activity of one of the three potent neutralizing antibodies (nAbs). Cryo-EM showed that the cocktail of other two nAbs simultaneously bound to all three RBDs. Furthermore, the nAb cocktail synergistically neutralized different SARS-CoV-2 pseudovirus strains, including the B.1.1.7.

biochemistry↗

bioRxiv2021

COVID-19 dominant D614G mutation in the SARS-CoV-2 spike protein desensitizes its temperature-dependent denaturation

The D614G mutation in the spike protein of SARS-CoV-2 alters the fitness of the virus, making it the dominant form in the COVID-19 pandemic. Here we demonstrated by cryo-electron microscopy that the D614G mutation does not significantly perturb the structure of the spike protein, but multiple receptor binding domains are in an upward conformation poised for host receptor binding. The impact of the mutation lies in its ability to eliminate the unusual cold-induced unfolding characteristics, and to significantly increase the thermal stability under physiological pH. Our findings shed light on how the D614G mutation enhances the infectivity of SARS-CoV-2 through a stabilizing mutation, and suggest an approach for better design of spike-protein based conjugates for vaccine development.

biochemistry↗

bioRxiv2021

Sialic acid-Dependent Binding and Viral Entry of SARS-CoV-2

Emerging evidence suggests that host glycans influence infection by SARS-CoV-2. Here, we reveal that the receptor-binding domain (RBD) of the spike (S)-protein on SARS-CoV-2 recognizes oligosaccharides containing sialic acid (SA), with preference for the oligosaccharide of monosialylated gangliosides. Gangliosides embedded within an artificial membrane also bind the RBD. The monomeric affinities (Kd = 100-200 M) of gangliosides for the RBD are similar to heparan sulfate, another negatively charged glycan ligand of the RBD proposed as a viral coreceptor. RBD binding and infection of SARS-CoV-2 pseudotyped lentivirus to ACE2-expressing cells is decreased upon depleting cell surface SA level using three approaches: sialyltransferase inhibition, genetic knock-out of SA biosynthesis, or neuraminidase treatment. These effects on RBD binding and pseudotyped viral entry are recapitulated with pharmacological or genetic disruption of glycolipid biosynthesis. Together, these results suggest that sialylated glycans, specifically glycolipids, facilitate viral entry of SARS-CoV-2.

biochemistry↗

bioRxiv2017

Multiple reference genome sequences of hot pepper reveal the massive evolution of plant disease resistance genes by retroduplication

Transposable elements (TEs) provide major evolutionary forces leading to new genome structure and species diversification. However, the role of TEs in the expansion of disease resistance gene families has been unexplored in plants. Here, we report high-quality de novo genomes for two peppers (Capsicum baccatum and C. chinense) and an improved reference genome (C. annuum). Dynamic genome rearrangements involving translocations among chromosome 3, 5 and 9 were detected in comparison between C. baccatum and the two other peppers. The amplification of athila LTR-retrotransposons, members of the gypsy superfamily, led to genome expansion in C. baccatum. In-depth genome-wide comparison of genes and repeats unveiled that the copy numbers of NLRs were greatly increased by LTR-retrotransposon-mediated retroduplication. Moreover, retroduplicated NLRs exhibited great abundance across the angiosperms, with most cases lineage-specific and thus recent events. Our study revealed that retroduplication has played key roles in the emergence of new disease-resistance genes in plants.

plant biology↗