Biology subjects

Jiang, Y. X.

Publications and source records attributed to Jiang, Y. X..

4 recordsLinked to original sources

bioRxiv2022

Contact Stiffness Governs Mechanoresponses of Living Cells to Extracellular Microenvironment

In interactions between cells and extracellular matrices (ECMs), contact mechanics theory indicates that local ECM deformation depends on both local and non-local forces imposed by cells. In the present study, we investigated the use of a comprehensive variable, contact stiffness (CS), to interpret cell-ECM interactions. CS defines the relationship between the local ECM deformation and the total force from a cell, integrating the effects of individual variables including ECM stiffness, ECM thickness, and cell adhesion area. Through assessments of ECM mechanosensing by human mesenchymal stem cells (hMSCs) under varied CS conditions, we showed that CS scaled well with both yes-associated protein (YAP) activity and the extent of stem cell differentiation. To reveal the cross-scale mechanism underlying mechanosensing, we propose a CS-based motor clutch model, which suggests that various mechanical stimuli affect cells by altering the CS, thus altering the reaction force from the ECM. Using the proposed model, we revealed the contributions of cell architecture evolution to stem cell differentiation and predicted the influence of a non-adjacent ECM layer on cellular mechanosensing. These results demonstrate that the use of CS provides a quantitative predictive framework that allows researchers to address longstanding questions about the effects of ECM mechanics on cell behaviors.

biophysics↗

bioRxiv2022

Amyloid fibrils in frontotemporal lobar degeneration with TDP-43 inclusions are composed of TMEM106B, rather than TDP-43

FTLD is the third most common neurodegenerative condition, following only Alzheimers and Parkinsons diseases. FTLD typically presents in 45-64-year-olds with behavioral changes or progressive decline of language skills. The subtype FTLD-TDP is characterized by certain clinical symptoms and pathological neuronal inclusions detected by TDP-43 immunoreactivity. Here, we extracted amyloid fibrils from brains of four patients, representing four out of five FTLD-TDP subclasses and determined their near-atomic resolution structures by cryo-EM. Unexpectedly, all amyloid fibrils examined are composed of a 135-residue C-terminal fragment of TMEM106B, a lysosomal membrane protein previously implicated as a genetic risk factor for FTLD-TDP. In addition to TMEM106B fibrils, abundant non-fibrillar aggregated TDP-43 is present, as revealed by immunogold labeling. Our observations confirm that FTLD-TDP is an amyloid-involved disease and suggest that amyloid involvement in FTLD-TDP is of protein TMEM106B, rather than of TDP-43.

molecular biology↗

bioRxiv2021

The SARS-CoV-2 nucleocapsid protein preferentially binds long and structured RNAs

The SARS-CoV-2 nucleocapsid protein (NCAP) functions in viral RNA genome packaging, virion assembly, RNA synthesis and translation, and regulation of host immune response. RNA-binding is central to these processes. Little is known how NCAP selects its binding partners in the myriad of host and viral RNAs. To address this fundamental question, we employed electrophoresis mobility shift and competition assays to compare NCAP binding to RNAs that are of SARS-CoV-2 vs. non-SARS-CoV-2, long vs. short, and structured vs. unstructured. We found that although NCAP can bind all RNAs tested, it primarily binds structured RNAs, and their association suppresses strong interaction with single-stranded RNAs. NCAP prefers long RNAs, especially those containing multiple structures separated by single-stranded linkers that presumably offer conformational flexibility. Additionally, all three major regions of NCAP bind RNA, including the low complexity domain and dimerization domain that promote formation of NCAP oligomers, amyloid fibrils and liquid-liquid phase separation. Combining these observations, we propose that NCAP-NCAP interactions that mediate higher-order structures during packaging also drive recognition of the genomic RNA and call this mechanism recognition-by-packaging. This study provides a biochemical basis for understanding the complex NCAP-RNA interactions in the viral life cycle and a broad range of similar biological processes. HIGHLIGHTSO_LINCAP primarily binds structured RNAs. C_LIO_LINCAP prefers multiple RNA structures separated by single-stranded linkers. C_LIO_LINCAP favors binding to long RNAs. C_LI

biochemistry↗

bioRxiv2021

Inhibition of amyloid formation of the Nucleoprotein of SARS-CoV-2

The SARS-CoV-2 Nucleoprotein (NCAP) functions in RNA packaging during viral replication and assembly. Computational analysis of its amino acid sequence reveals a central low-complexity domain (LCD) having sequence features akin to LCDs in other proteins known to function in liquid-liquid phase separation. Here we show that in the presence of viral RNA, NCAP, and also its LCD segment alone, form amyloid-like fibrils when undergoing liquid-liquid phase separation. Within the LCD we identified three 6-residue segments that drive amyloid fibril formation. We determined atomic structures for fibrils formed by each of the three identified segments. These structures informed our design of peptide inhibitors of NCAP fibril formation and liquid-liquid phase separation, suggesting a therapeutic route for Covid-19. One Sentence SummaryAtomic structures of amyloid-driving peptide segments from SARS-CoV-2 Nucleoprotein inform the development of Covid-19 therapeutics.

biochemistry↗