Volume 20 Issue 6, June 2024

Screening of a chemical library identifies a novel ferroptosis inhibitor that directly interferes with the formation of intracellular membrane contacts between the endoplasmic reticulum (ER) and mitochondria (ERMCS), commonly referred to as mitochondria-associated membranes (MAMs).

Labeling of endogenous proteins with chemical probes is highly desirable for life science studies. The combination of RNA base editing and site-specific incorporation of non-canonical amino acids allows the introduction of small chemical tags into endogenous proteins in living cells.

Developing therapeutic agents that target the peptidylarginine deiminase PAD4 requires better understanding of the function of the enzyme. Isozyme-selective antibodies that alter PAD4 activity have been identified recently, revealing unique modes of action.

Natural ribozymes can cleave RNA and single-stranded DNA (ssDNA) by transesterification or a blend of hydrolytic and transesterification reactions. Now, ribozymes have been discovered that catalyze the hydrolytic cleavage of ssDNA. Similar ribozymes could potentially replace large, immunogenic, protein-based nucleases in gene therapies.

The ZDHHC family of palmitoyl transferases lipidates numerous protein targets, but the paucity of selective inhibitors has hindered their target profiling. A generalized chemical genetic system can now map the protein targets of individual ZDHHC family members.

Targeted protein degradation has emerged as a promising approach in drug discovery, harnessing a cell’s intrinsic machinery to eliminate disease-related proteins. Now, a study paves the way to translating this technology into potential anti-mycobacterial therapies, by exploiting the bacterial protein-degradation complex.

Nonribosomal peptide synthetases produce diverse natural products, including many valuable therapeutics. Although the condensation domains that catalyze peptide bond formation in these multifunctional enzymes have been difficult to engineer, a yeast display system that was developed to screen millions of variants now enables efficient reprogramming of synthetase substrate specificity.

CRISPR–Cas13 systems use single-subunit RNA-guided Cas13 effectors for targeted RNA recognition and cleavage. This Review summarizes the recent advances in understanding the structural and mechanistic aspects of Cas13 systems and the diverse applications of these systems in biotechnology and therapeutics.

Using single-molecule and biochemical methods, Göse et al. demonstrated that the helicase-like ATPase of a Type III restriction enzyme establishes DNA sliding through a sequential series of nucleoprotein remodeling steps driven by DNA translocation.

A small molecule, CGI1746, was identified to block ferroptosis acting through the sigma-1 receptor, a chaperone primarily at endoplasmic reticulum–mitochondria contacts to mediate calcium transfer.

Qin et al. find that cell detachment induces condensation of LATS2, a core kinase of the Hippo pathway. These LATS2 condensates protect LATS2 from degradation by the ubiquitin–proteasome system, thereby promoting the assembly of Hippo signalosomes for pathway activation.

Hao et al. developed a method termed RNA editing-mediated noncanonical amino acids protein tagging (RENAPT), which combines RNA editing and genetic code expansion techniques to label endogenous proteins for real-time imaging in living cells.

SUGAR-TARGET is a modular platform for the homogeneous synthesis of enzymes with controlled N-linked glycosylation using a one-step immobilization/purification method.

Unbiased antibody discovery identified allosteric regulators of PAD4, revealing mechanisms to alter PAD4’s activity and providing tools to study rheumatoid arthritis.

The study demonstrates that specific recognition and custom binding geometries can be computationally encoded between protein spans within lipids through designing synthetic transmembrane proteins to functionally regulate a target cytokine receptor.

Nonribosomal peptide synthetases produce valuable natural products but are challenging to engineer. Yeast surface display and fluorescence-activated cell sorting have now been combined to reprogram a condensation domain to recognize a noncanonical lipid substrate. This methodology may facilitate molecular tailoring of many biosynthetic assembly lines.

A chemoproteomic method was developed that enables the global discovery of metal-binding proteins (MBPs) in proteomes, where the thermal stability of MBPs is perturbed by metal chelators. This tool, called METAL-TPP, is used to discover MBP candidates in the human proteome and provides a valuable method for functional annotation of MBPs in cell biology.

NinaB is an isomerooxygenase that generates visual chromophore (11-cis-retinal) from carotenoid substrates. Here Solano et al. reveal the structural basis for NinaB isomerase activity, providing new insights into the evolution of visual chromophore synthesis by carotenoid cleavage enzymes.