Volume 17 Issue 9, September 2021

Dan Tawfik suddenly left us on 4 May, 2021. His scientific intuition led him to articulate, and solve, many key questions related to protein chemistry and molecular evolution. Although science, particularly for his students, postdoctoral fellows and colleagues, is dimmer after his loss, his legacy will persist.

LYTACs induce selective degradation of extracellular proteins by recruiting them to cellular receptors that mediate delivery to the lysosome. Recent development of GalNAc-LYTACs and MoDE-As targeting the liver-specific ASGPR enables cell-type-restricted lysosomal protein degradation and reveals new LYTAC design principles.

RNA knot-like structures function as an efficient physical barrier to RNA exoribonucleases. Single-molecule mechanical manipulation is used to unfold these structures and unravel the cause of their unusual mechanical resistance from a different direction.

Liquid–liquid phase separation, yielding membraneless organelles, allows for the sequestration and functional insulation of cellular proteins. A modularly built, synthetic membraneless organelle platform enables efficient control over endogenous cellular activities by knockdown of protein function or controlled protein release.

Lysosome-targeting chimeras (LYTACs) based on glycan ligands of the asialoglycoprotein receptor facilitate the cell-specific targeting and turnover of proteins by lysosomal enzymes, expanding the scope of LYTAC-mediated targeted protein degradation.

Bifunctional ‘MoDE-A’ molecules, which contain ligands that bind to an extracellular protein and carbohydrate residues that recruit it to the asialoglycoprotein receptor, mediate cellular uptake and lysosomal turnover of target proteins.

The development of Sulfopin, a highly selective and potent, covalent Pin1 inhibitor that phenocopies Pin1 knockout and regresses tumors in murine and zebrafish models of neuroblastoma as well as in a pancreatic cancer mouse model.

Reconstitution studies reveal design principles by which a minimal 3-protein module differentially regulates the dynamics of spatially proximal crosslinked and noncrosslinked microtubules, mimicking microtubule array dynamics in the mitotic spindle.

A knot-like RNA from Zika virus is shown to evade digestion by host RNases through its extreme resistance to mechanical unfolding. Weakening the knot mechanically or reducing the likelihood of knot formation lowers the RNase resistance.

Deploying two unrelated CRISPR nucleases in tandem, with multiplexed CRISPR RNAs and a chemically stabilized activator, creates a simple, one-step assay that can rapidly detect attomolar concentrations of RNA without needing target amplification.

The cystic fibrosis transmembrane conductance regulator anion channel can adopt an alternate conformation of its nucleotide-binding domain, which affects channel activity and, under certain conditions, leads to unfolding and protein degradation.

Controlled assembly of synthetic intracellular condensates from engineered disordered proteins enables control of cellular activities such as proliferation and division through recruitment, sequestration and insulation of endogenous client proteins.