The LOV2 domain is commonly harnessed as a source of light-based regulation in engineered optogenetic switches. In prior work, we used LOV2 to create a light-regulated Dihydrofolate Reductase (DHFR) enzyme and showed that structurally disperse mutations in DHFR were able to tune the allosteric response to light. However, it remained unclear how light allosterically activates DHFR, and how disperse mutations modulate the allosteric effect.
View Article and Find Full Text PDFACS Pharmacol Transl Sci
November 2024
is commonly mutated in cancer, giving rise to loss of wild-type tumor suppressor function and increases in gain-of-function oncogenic roles. Thus, inhibition of mutant p53 and reactivation of wild-type function represents a potential means to target diverse tumor types. ()-1-(4-Methylpiperazin-1-yl)-3-(5-nitrofuran-2-yl)prop-2-en-1-one (NSC59984), first identified from a high-throughput screen, induces wild-type p53 signaling and antiproliferative effects while inhibiting mutant p53 gain-of-function activities.
View Article and Find Full Text PDFCold Spring Harb Perspect Biol
April 2024
Homologous protein sequences are wonderfully diverse, indicating many possible evolutionary "solutions" to the encoding of function. Consequently, one can construct statistical models of protein sequence by analyzing amino acid frequency across a large multiple sequence alignment. A central premise is that covariance between amino acid positions reflects coevolution due to a shared functional or biophysical constraint.
View Article and Find Full Text PDFHsp90 and Hsp70 are highly conserved molecular chaperones that help maintain proteostasis by participating in protein folding, unfolding, remodeling and activation of proteins. Both chaperones are also important for cellular recovery following environmental stresses. Hsp90 and Hsp70 function collaboratively for the remodeling and activation of some client proteins.
View Article and Find Full Text PDFButyrophilin 1A1 (BTN1A1) is implicated in the secretion of lipid droplets from mammary epithelial cells as a membrane receptor, which forms a secretion complex with the redox enzyme, xanthine oxidoreductase (XDH). The first evidence that BTN1A1 functions in this process was the generation of mouse lines, in which lipid secretion was disrupted and large unstable droplets were released into alveolar spaces with fragmented surface membranes. We have revisited one of these mutant mouse lines using RNAseq and proteomic analysis to assess the consequences of ablating the gene on the expression of other genes and proteins.
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