ABSTRACT
Talin-1 is the core mechanosensitive adapter protein linking integrins to the cytoskeleton. The TLN1 gene is comprised of 57 exons that encode the 2,541 amino acid TLN1 protein. TLN1 was previously considered to be expressed as a single isoform. However, through differential pre-mRNA splicing analysis, we discovered a cancer-enriched, non-annotated 51-nucleotide exon in TLN1 between exons 17 and 18, which we refer to as exon 17b. TLN1 is comprised of an N-terminal FERM domain, linked to 13 force-dependent switch domains, R1-R13. Inclusion of exon 17b introduces an in-frame insertion of 17 amino acids immediately after Gln665 in the region between R1 and R2 which lowers the force required to open the R1-R2 switches potentially altering downstream mechanotransduction. Biochemical analysis of this isoform revealed enhanced vinculin binding, and cells expressing this variant show altered adhesion dynamics and motility. Finally, we showed that the TGF-ß/SMAD3 signaling pathway regulates this isoform switch. Future studies will need to consider the balance of these two TLN1 isoforms.
Subject(s)
Neoplasms , Talin , Humans , Talin/genetics , Mechanotransduction, Cellular , Exons/genetics , Adaptor Proteins, Signal TransducingABSTRACT
Artificial molecular machines synthesized in supramolecular chemistry have attracted great interest over the past decades. DNA origami presents an alternative approach to construct nano-machines by directly designing its thermodynamically stable state by DNA sequences. Here, we construct a molecular device, named NanoMuscle, with mechanically interlocked DNA origami. NanoMuscle's configuration - either extended or contracted - can be controlled by adding specific DNA strands. We monitored NanoMuscle's multistep synthesis with gel electrophoresis, and verified that monomers of the NanoMuscle are interlocked at correct orientation with transmission electron microscopy (TEM). We then validated that NanoMuscle can switch between extended and contracted configuration. By converting binding energy from DNA hybridization and Brownian motion to mechanical movements, NanoMuscle may serve as a novel building block for future mesoscale machinery.
Subject(s)
DNA/chemistry , Motion , Muscles , Nanostructures/chemistry , Nanotechnology , Nucleic Acid HybridizationABSTRACT
Three new 8-hydroxybriaranes-fragilides R-T (1-3) were obtained from a sea whip gorgonian coral Junceella fragilis. The structures of briaranes 1-3 were elucidated by using spectroscopic methods, including 1D (1H and 13C NMR), 2D (COSY, HSQC, HMBC, and NOESY experiments) NMR studies, and (+)-HRESIMS. Fragilides S and T (2 and 3) are the only briaranes known to possess 8α-hydroxy and 17ß-methyl groups, respectively. Briarane 2 exerted an inhibition effect on iNOS release from RAW264.7; a macrophage cell line that originated from a mouse monocyte macrophage, stimulated with lipopolysaccharides.
