Volume 31 Issue 2, February 2024

Ubiquitination is an essential process that curtails cellular levels of damaged and redundant proteins. Chemical biologists have harnessed this natural system to induce the degradation of disease-relevant proteins. We reflect here on the potential of ‘degraders’ for targeted selectivity, and discuss the role of computer-aided drug design in shaping future advances.

In addition to its role in proteasomal degradation, ubiquitin has multiple roles in autophagy. It can mark proteins for autophagic degradation and actively drive autophagosome formation. Recent work shows that ubiquitin can also be conjugated to phospholipids and other biomolecules.

The modification of proteins with the small protein ubiquitin constitutes a Daedalian system of posttranslational modifications in every eukaryotic cell, which is often referred to as the ubiquitin code¹. Here we consider the scale and complexity of the ubiquitin system in light of recent developments.

Here, the authors show how Aurora kinase A (AURKA) employs Rab1a to direct ER remodeling. Activated Rab1A is retained on the ER and directly interacts with the RTN/REEP ER-shaping machinery to promote its oligomerization, eventually triggering an increase of ER complexity during mitosis.

Autophagy is essential for cellular homeostasis which decreases with age. Here, the authors identify aging-induced reduction of DHHC5-mediated beclin 1 palmitoylation as an underlying mechanism by which aging induces autophagy decline in the brain.

In intracellular trafficking, transport vesicles deliver cargo via membrane fusion. The fusion machinery includes both tethering factors and SNAREs. The cryo-electron microscopy structure of a tether–SNARE complex reveals the basis for their collaboration.

Authors provide analysis of starch-binding protein Sas6, from Ruminococcus bromii, a bacterium that degrades resistant starch granules in the human gut, and demonstrate how carbohydrate-binding modules recognize different moieties within starch.

Here, using cryo-EM, the authors delineate how the chromatin remodeling complex of ISWIa binds dinucleosomes. Their findings showcase synergistic interactions between ISWIa subumnits and neighboring nucleosomes, thus exemplifying the nucleosome spacing activity of ISWIa.

Here authors developed a computational method to design complicated all-α structures using typical helix–loop–helix motifs and canonical α-helices, and demonstrated the ability to create complicated all-α proteins.

How do intrinsically disordered proteins behave inside the cell? Moses et al. show that these flexible proteins contain structural preferences inside cells, and that these preferences can change with the composition of the intracellular environment.

Here, the authors solve sequential structures of binding by the transcription activators NtcA and NtcB, showing that they cooperatively induce looping back of the promoter DNA towards RNA polymerase allowing transcription activation through a DNA looping mechanism.

Here, using cryo-EM, in vitro and cellular assays, the authors elucidate how SS18–SSX1, via an unorthodox manner of selectively recognizing ubiquitylated nucleosomes, hijacks the BAF1 complex to Polycomb-repressed regions in synovial carcinoma.

Using structural, biochemical, and functional assays, the authors demonstrate that the E3 ligase KLHDC2, via newly developed small-molecule ligands, can be co-opted to target critical targets for degradation.

Here, the authors demonstrate that CAND1 increases the dissociation rate of CRL2s, thus exerting an inhibitory effect, which in turn endows CRL2s with a selectivity for different targets based on their affinity for CRL2, thereby pacing protein degradation.

Here, upon obtaining cryo-EM structures of CRL3^KBTBD2 in seven states, the authors propose a model for the activation cycle of CRL3 ligases, including assembly, substrate recruitment, (de)neddylation and CAND1-mediated substrate receptor exchange.

The ubiquitin E3 ligase UBR4 is a key component of the ubiquitin N-degron pathway, but the domain that catalyzes ubiquitin transfer remains unknown. Here the authors identify its unorthodox E3 module and characterize its structure and ubiquitin transfer mechanism.

Using cryo-EM, SAXS and HDX–MS, the authors mechanistically delineate dimerization-induced autoinhibition of the HECT-type ligase HACE1 and the selectivity of the active ligase monomer for GTP-bound RAC1.

The authors define a NEDD8-activated cullin-RING E3 poly-ubiquitylation mechanism using chemistry, cryo-EM and rapid kinetics. Near-perfect catalytic efficiency is achieved by an E2 ‘synergy loop’ connecting to the E3, donor and acceptor ubiquitins.