Disease-related mutations in PI3Kγ disrupt regulatory C-terminal dynamics and reveal a path to selective inhibitors

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.

elifesciences.org

An MR1-specific nanobody capable of blocking MR1T cell activation

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

academic.oup.com

Cryo-EM structure of yeast telomerase

YouTube video by MRC Laboratory of Molecular Biology

youtube.com

Proposals

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Phospholipids in Aging and Disease.

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

events.faseb.org

Distinct impact of PI(4)P flux on PI(4,5)P2 steady states and oscillations | PNAS

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

pnas.org

The Lipid Interactome: an interactive and open access platform for exploring cellular lipid–protein interactions

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

doi.org

cPLA2α targeting to exosomes connects nuclear deformation to LTB4-signaling during neutrophil chemotaxis

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

science.org

Research Group Leader Tenure Track - Structural Studies - LMB 2775 - Medical Research Council

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

mrc.tal.net

The GTPase activating protein Gyp6 binds Retromer and inactivates Rab7/Ypt7 to coordinate the formation of endosomal carriers

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

biorxiv.org

The Government of Canada introduces new programs for international researchers - Canada.ca

canada.ca

A proximity map of RAB GTPases delineates roles for RAB14 in EARP complex and UHRF1BP1 endosomal recruitments

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...

nature.com

Structural basis for the recruitment and selective phosphorylation of Akt by mTORC2

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...

science.org

Design, Synthesis, and Biological Evaluation of Mono- and Diamino-Substituted Squaramide Derivatives as Potent Inhibitors of Mycobacterial Adenosine Triphosphate (ATP) Synthase

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...

pubs.acs.org

ATG2 is a triglyceride transfer protein | PNAS

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

pnas.org

jbc.org

Discovery, Optimization, and Anticancer Activity of Lipid-Competitive Pleckstrin Homology Domain-Containing Family A Inhibitors

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.

pubs.acs.org

Molecular basis for regulation of the class I phosphoinositide 3-kinases (PI3Ks), and their targeting in human disease

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

sciencedirect.com

Molecular insight on the role of the phosphoinositide PIP3 in regulating the protein kinases Akt, PDK1, and BTK

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...

portlandpress.com