The c-terminus of PI3K plays a key role in regulating kinase activity, with c-terminal disease-linked mutations leading to either activation or inhibition, which reveal a path to specific inhibitors.

Abstract. MR1 is a non-polymorphic, ubiquitously expressed, MHC class I-like antigen-presenting molecule that presents small-molecule metabolites to T cell

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Explore breakthroughs in phospholipid research, membrane biology, and aging at this leading scientific conference.

Plasma membrane (PM) phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] regulates indispensable processes such as exocytosis, endocytosis, and actin...

AbstractSummary. Lipid–protein interactions play essential roles in cellular signaling and membrane dynamics, yet their systematic characterization has lon

Nuclear squeezing triggers lipid signals that help neutrophils stay on course through tight spaces.

Location: Cambridge. Vacancy: Research Group Leader Tenure Track - Structural Studies - LMB 2775. Closing Date: 16/03/2026, 23:55

The Retromer coat is conserved in all eukaryotes and is crucial for the correct intracellular sorting of many transmembrane receptors and lysosomal hydrolases. Retromer is an effector of the late endosomal small GTPase RAB7 and is also implicated in its inactivation required for proper endosomal maturation. Here, we explore the role of controlled GTP hydrolysis by the RAB7 ortholog Ypt7 in the formation of Retromer-coated membrane carriers in yeast. Proximity labelling and genetic ablation identify the GTPase Activating Protein (GAP) Gyp6 as a critical regulator of Ypt7 activity in the context or Retromer. Structural studies show that Retromer recruits Gyp6 through its Vps29 subunit, which recognises a specific PL motif and a secondary binding site in the C-terminal domain of Gyp6. This interaction does not occur with other yeast GAPs. Ablation of the Gyp6-Retromer interface or the catalytic activity of Gyp6 leads to the accumulation of tubular structures on endo-lysosomal compartments and to increased association of Ypt7 with Retromer and its cargo Vps10. These results support a model in which Gyp6 controls the switch from Ypt7-dependent Retromer coat assembly and cargo collection to the departure of the carrier through membrane fission and uncoating. ### Competing Interest Statement The authors have declared no competing interest. National Health and Medical Research Council, https://ror.org/011kf5r70, APP2016410 Swiss National Science Foundation, https://ror.org/00yjd3n13, 31003A_179306, 310030_204713, 10.006.083

Communications Biology - Proximity labeling proteomics of RAB GTPases identifies an array of neighboring RAB proteins. Functional validation studies reveal links between RAB25 and DENND6A, or...

The mTOR protein kinase forms two multiprotein complexes, mTORC1 and mTORC2, that function in distinct signaling pathways. mTORC1 is regulated by nutrients, and mTORC2 is a central node in phosphoinos...

Amides of squaric acid are new drug candidates with activity against mycobacteria. Like the approved drug bedaquiline, these compounds achieve efficacy by inhibiting mycobacterial ATP synthase. Howeve...

Bridge-like lipid transfer proteins (BLTPs) are established to function in phospholipid transport between bilayers at organelle–organelle contact s...

Phosphoinositide signaling is a major cellular mechanism controlling cancer cell viability, proliferation, and survival. Yet, inhibition of lipid kinases that produce oncogenic phosphoinositides has afforded only a limited number of efficacious drugs attributed in large part to on-target toxicity resulting from the pleiotropic effects of these signaling lipids. Targeting the specific phosphoinositide effector pathways via competitive inhibitors of phosphoinositide-recognizing pleckstrin homology (PH) domains represents a relatively unexplored means to achieve greater specificity. Herein, we present the discovery from in silico screening, structure–activity relationship (SAR) optimization, and cellular characterization of novel phosphoinositide-competitive inhibitors of the pleckstrin homology domain-containing A (PLEKHA) family. These compounds induce cytotoxic effects in BRAF and NRAS mutant melanoma cells, consistent with on-target inhibition, and the most potent compound is activated by endogenous esterase activity, suggesting that prodrug esters represent a viable strategy for targeting the phosphoinositide-binding pockets of the PLEKHA family of PH domains.

The class I phosphoinositide 3-kinase pathway (PI3K) is a master regulator of cellular growth, and plays essential roles in controlling immune cell fu…

Protein kinases are master regulators of myriad processes in eukaryotic cells playing critical roles in growth, metabolism, cellular differentiation, and motility. A subclass of protein kinases is reg...

Join us at Chemsymposia 2026 to discover groundbreaking research in physics applications. Connect with experts, engage in insightful discussions, and explore our venue, registration details, and speak...

PI3Kα is a potent oncogene that converts PIP2 to PIP3 at the plasma membrane upon activation by receptor tyrosine kinases and Ras GTPases. In the absence of any structures of activated PI3Kα, the mole...

In this paper, Pemberton et al. describe the generation and characterization of an engineered active fragment of the PIKfyve enzyme and its use to generate

A dynamic substrate adapter (DET1) recruits COP1 to Cullin ubiquitin ligase complexes assisted by a noncatalytic E2 enzyme.

Holmes and colleagues show that AKT activation is blocked by commonly used PIP3 biosensors, but that this can be overcome by expressing biosensors at singl

The mu-opioid receptor (MOR) is a major target for the treatment of pain. However, opioids are prone to side effects which limit their effectiveness as analgesics and can lead to opioid use disorders ...

The structure of the EFR3A-PI4KA complex reveals insight into PI4KA membrane localization and its role in human disease.