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A small molecule, CLEO4-88, was identified that acts as a molecular glue, linking the E3 ligase subunit GID4 with ACAA1. Instead of triggering ACAA1 degradation, the compound inhibits its enzymatic activity.

All RAF kinase domain structures reported to date have adopted a dimer configuration. Marc Therrien, Frank Sicheri and colleagues now report a crystal structure of the BRAF monomeric 'off' state, providing insight into its catalytic activation.

Antibody diversification relies on the intentional mutagenesis of immunoglobulin genes for adaptive immune responses. Here, the authors identified a CTLH E3 ubiquitin ligase complex that co-opts FAM72A to recruit and degrade the UNG2 base excision repair factor to permit mutagenesis.

A monobody was identified that binds to an allosteric lobe at the α4-β6-α5 interface to block H- and K-RAS signaling and transformation by disrupting RAS dimerization and nanoclustering.

Determinants of WEE1 inhibitor sensitivity in cancer cells are largely undefined. Here, the authors show that WEE1 inhibitors beyond their cell cycle perturbing effects also lead to paradoxical activation of the integrated stress response kinase GCN2.

It is just as important to shut off a signaling pathway as it is to turn it on. A new study on the tandem Ras-associating (RA) and pleckstrin-homology (PH) domains of Grb10 and Grb14 provides important insight into a multicomponent assembly for downregulating insulin receptor signaling.

tRNA modifications are vital for their function in protein synthesis, one of the most central processes in all living cells. Here the authors show how KEOPS, a multi-subunit tRNA modifying complex, engages and acts on a substrate tRNA.

Using biochemistry, cell biological, X-ray crystallography and cryo-EM methods, Maisonneuve et al. reveal how the scaffolding proteins CNK and HYP enhance the binding of KSR to MEK, which in turn allosterically controls RAF activation in Drosophila.

Structures of an unusual enzymatic domain in PINK1 provide insights into how this protein regulates the function of organelles called mitochondria, and how mutations in PINK1 contribute to Parkinson’s disease.

The BRCC36 isopeptidase complex (BRISC) is a deubiquitylase that stabilizes interferon receptors, driving inflammation. We discovered ‘BRISC molecular glue’ inhibitors (BLUEs) that selectively inactivate BRISC, promoting interferon receptor ubiquitylation and degradation to dampen immune responses.

This study identifies a deubiquitinase (DUB) that specifically recognises and cleaves linear ubiquitin chains, implicating linear (de)ubiquitination in Wnt signalling and angiogenesis; mutations in gumby cause defects in angiogenesis in mice, and structural and biochemical analysis shows that gumby encodes a linear-ubiquitin-specific DUB.

KEOPS is an evolutionary conserved complex with a core of four core subunits—Pcc1, Kae1, Bud32 and Cgi121—that catalyzes the universal and essential tRNA modification N⁶-threonylcarbamoyl adenosine (t⁶A). Here the authors describe a Cgi121-tRNA crystal structure and new composite model of the KEOPS holo-enzyme-substrate complex that shed light on the t⁶A catalytic cycle and its regulation.

A PROTAC termed P4B targeting BRAF V600E mutant has been developed, which displays enhanced inhibitory function in cell lines carrying BRAF mutations that impart resistance to conventional BRAF inhibitors.

Modulation of the unfolded protein response by targeting IRE1 has several potential therapeutic applications. Here, the authors provide a first structural view of inhibitors engaging the RNase-active site of IRE1 that suggests avenues towards the generation of analogues with increased potency and selectivity.

Activation of the kinase RAF, a member of the ERK (extracellular signal-regulated kinase) pathway, is triggered by the binding of growth factors to receptor tyrosine kinases. Activating mutations in RAF can lead to unbridled signalling through the ERK pathway and have been linked to several human cancers. Here, the activation mechanism of RAF is shown to involve a specific mode of dimerization of its kinase domain, which is relevant for the action of the RAF activator KSR and certain oncogenic mutations.

Although general inhibitors of the ubiquitin-proteasome system have been reported, compounds targeting specific ubiquitylation enzymes should be beneficial in clinical applications and basic research. Orlicky et al. present an allosteric inhibitor specific to the yeast SCF^Cdc4 E3 ligase that prevents binding of the target protein to the WD40 domain of the complex.

ATP-competitive RAF kinase inhibitors stabilize a closed and rigid active conformation of the RAF kinase domain, which leads to RAF dimerization and allosteric activation of the inhibitor-free protomer.

In the ubiquitin-proteasome system, E2 enzymes such as Cdc34A mediate the transfer of ubiquitin to protein substrates, which are thus marked for proteasomal degradation or other fates. New structural data reveal that the small-molecule inhibitor CC0651 impairs Cdc34A activity by stabilizing the normally transient Cdc34A–ubiquitin complex.

The antidiabetic action of metformin raises heptocyte intracellular AMP levels, causing allosteric inhibition of fructose-1,6-bisphosphatase and thus reductions in gluconeogenesis.

This study shows that 53BP1 recruitment to sites of DNA damage involves dual recognition of H4K20me2 and H2AK15 histone ubiquitination; the ubiquitin mark and the surrounding epitope on H2A are read by a region of 53BP1 designated the ubiquitination-dependent recruitment motif.

The WD40 domain of the SCF^Cdc4ubiquitin ligase targets substrates via multiple phosphorylated degron motifs. The authors define a second degron-binding WD40 pocket that imparts a negative allosteric effect on binding to the primary pocket, and thereby enables the dynamic exchange of bound degrons.

When double-strand breaks occur in eukaryotic DNA, the chromatin that protects and organizes the genome must be removed from the vicinity of the break to allow repair factors to bind. Such chromatin displacement involves the addition of ubiquitin groups to histone proteins near the break by the ubiquitin ligases RNF8 and RNF168. Here it is shown that the enzyme OTUB1 prevents RNF168-dependent poly-ubiquitination. Pharmacological targeting of this process might enhance the DNA damage response.

Additional sex combs-like (ASXLs) stimulate BAP1 deubiquitinase activity to induce tumor suppression, but how these complexes work in coordination in vivo is unclear. Here, the authors show the mutually reinforcing roles of BAP1 and ASXLs such that BAP1 promotes DEUBAD monoubiquitination of ASXL2, which in turn stimulates BAP1 DUB activity.

The Hippo pathway is frequently dysregulated in cancer. Here, the authors identify NUAK2 as negative regulator of the Hippo pathway from a siRNA kinome screen and show that NUAK2 promotes YAP/TAZ nuclear localisation while NUAK2 is a transcriptional target of YAP/TAZ, thus providing a feed forward loop to promote tumorigenesis.

A cryo-electron microscopy structure of the DNA damage repair protein 53BP1 bound to a nucleosome illuminates the way 53BP1 recognizes two types of histone modifications (a methyl group and a ubiquitin moiety), and provides insight into the highly specified recognition and recruitment of 53BP1 to modified chromatin.

KSR–MEK complexes allosterically activate BRAF through the action of N-terminal regulatory region and kinase domain contacts, thus challenging the accepted role of KSR as a scaffold for MEK recruitment to RAF.

This study finds germline loss-of-function mutations in HAVCR2, which encodes the immune modulator TIM-3, in individuals with subcutaneous panniculitis-like T cell lymphomas and hemophagocytic lymphohistiocytosis, a life-threatening inflammatory condition.

Modulation of DNA repair pathway choice by a potent inhibitor of 53BP1 improves the efficiency of homology-dependent genome editing in human and mouse cells.